Cdr Clinical Review Report for Truvada

Common Drug Review Clinical Review Report

August 2016

Drug emtricitabine/tenofovir disoproxil fumarate (Truvada)

For use in combination with safer sex practices for pre‐exposure Indication prophylaxis to reduce the risk of sexually acquired HIV‐1 infection in adults at high risk.

Listing request As per indication

Dosage form(s) emtricitabine/tenofovir disoproxil fumarate 200 mg/300 mg tablets

NOC date February 23, 2016

Manufacturer Gilead Sciences Canada, Inc.

Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.

While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.

CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials.

This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the third-party website owners’ own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites.

Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada’s federal, provincial, or territorial governments or any third party supplier of information.

This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at the user’s own risk.

This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada.

The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.

Redactions: Confidential information in this document has been redacted at the request of the manufacturer in accordance with the CADTH Common Drug Review Confidentiality Guidelines.

About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.

Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec. CDR CLINICAL REVIEW REPORT FOR TRUVADA

TABLE OF CONTENTS

ABBREVIATIONS ...... iii EXECUTIVE SUMMARY ...... iv 1. INTRODUCTION ...... 1 1.1 Disease Prevalence and Incidence ...... 1 1.2 Standards of Therapy ...... 1 1.3 Drug ...... 2 2. OBJECTIVES AND METHODS ...... 3 2.1 Objectives ...... 3 2.2 Methods ...... 3 3. RESULTS ...... 5 3.1 Findings From the Literature ...... 5 3.2 Included Studies ...... 9 3.3 Patient Disposition ...... 17 3.4 Exposure to Study Treatments ...... 18 3.5 Critical Appraisal ...... 19 3.6 Efficacy ...... 20 3.7 Harms...... 25 4. DISCUSSION ...... 28 4.1 Summary of Available Evidence ...... 28 4.2 Interpretation of Results ...... 28 4.3 Potential Place in Therapy ...... 32 5. CONCLUSIONS ...... 33 APPENDIX 1: PATIENT INPUT SUMMARY ...... 34 APPENDIX 2: LITERATURE SEARCH STRATEGY ...... 38 APPENDIX 3: EXCLUDED STUDIES ...... 42 APPENDIX 4: DETAILED OUTCOME DATA ...... 43 APPENDIX 5: SUMMARY OF OPEN‐LABEL EXTENSION STUDY WITH PARTICIPANTS FROM MSM PrEP STUDIES ...... 49 APPENDIX 6: SUMMARY OF THE PILOT PHASE OF THE PROUD STUDY ...... 55 APPENDIX 7: SUMMARY OF THE DOUBLE‐BLIND PHASE OF THE IPERGAY STUDY ...... 60 REFERENCES ...... 66

Tables Table 1: Summary of Results ...... viii Table 2: Inclusion Criteria for the Systematic Review ...... 3 Table 3: Details of the iPrEx Study (Men Who Have Sex With Men)...... 6 Table 4: Details of the Partners PrEP Study (Heterosexual Serodiscordant Couples) ...... 7 Table 5: Details of the CDC TDF2 Study (Heterosexual Men and Women) ...... 8 Table 6: Summary of Baseline Characteristics of iPrEx Study (MSM) ...... 10 Table 7: Summary of Baseline Characteristics of Partners PrEP Study (Serodiscordant Heterosexual Couples) ...... 12

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

Table 8: Summary of Baseline Characteristics of CDC TDF2 Study (Heterosexual Men and Women) ...... 12 Table 9: Additional Interventions at Monthly Visits ...... 14 Table 10: Patient Disposition ...... 17 Table 11: Retention of Participants Over Time in the Partners PrEP Study ...... 18 Table 12: Pregnancies in the Partners PrEP Study ...... 18 Table 13: Duration of Exposure to Study Drug in the iPrEx Study; Safety Set ...... 19 Table 14: HIV‐1 Seroconversion; Modified Intention‐to‐Treat Set ...... 22 Table 15: Post‐Exposure Prophylaxis in the iPrEx Study; Modified Intention‐to‐Treat Set ...... 22 Table 16: Antiretroviral Therapy Use by HIV‐1–infected Participants in the Partners PrEP Study; Safety Set ...... 23 Table 17: Plasma Emtricitabine and Tenofovir Levels by HIV‐1 Infection Status ...... 23 Table 18: Harms; Safety Set ...... 26 Table 19: HIV‐1 Seroconversion in the iPrEx Study at Different Cut‐off Dates; Modified Intention‐to‐Treat Set ...... 43 Table 20: Subgroup Analysis According to Sex of Primary Efficacy End Point; Modified Intention‐to‐Treat Set ...... 43 Table 21: Receptive Anal Intercourse and Protected Anal Intercourse Over Time in the iPrEx Study; Safety Set ...... 44 Table 22: Proportion of Participants Reporting Any Unprotected Sex and Outside Sex Partners in the Previous Month in the Partners PrEP Study; Safety Set ...... 45 Table 23: Participants with Sexually Transmitted Infections by Visit in the iPrEx Study ...... 45 Table 24: Outside Sexual Partners and Incidence of Sexually Transmitted Infections in the Partners PrEP Study; Safety Set ...... 46 Table 25: Sexually Transmitted Infection Adverse Events in the CDC TDF2 Study; Safety Set ...... 46 Table 26: Adherence to Study Drug in the iPrEx Study; Safety Set ...... 47 Table 27: Adherence to Study Drug in the Partners PrEP Study; Safety Set ...... 47 Table 28: Harms in the iPrEx Study According to Manufacturer Analysis; Safety Set ...... 47 Table 29: Patient Disposition ...... 50 Table 30: Baseline Characteristics ...... 51 Table 31: Effect of Tenofovir Diphosphate in Dried Blood Spot on HIV Infection ...... 53 Table 32: Patient Disposition ...... 56 Table 33: Baseline Characteristics ...... 57 Table 34: Bacterial Sexually Transmitted Infections ...... 58 Table 35: Patient Disposition ...... 61 Table 36: Baseline Characteristics ...... 62 Table 37: Adherence to Intervention Based on Patient Self‐report for the Last Sexual Intercourse ...... 64 Table 38: Adverse Events ...... 64

Figure Figure 1: Flow Diagram for Inclusion and Exclusion of Studies ...... 5

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

ABBREVIATIONS

AE adverse event ART antiretroviral therapy CDC Centres for Disease Control and Prevention CDR CADTH Common Drug Review CI confidence interval DB double‐blind FDA Food and Drug Administration FDC fixed‐dose combination FTC emtricitabine FTC/TDF emtricitabine/tenofovir disoproxil fumarate HIV‐1 human immunodeficiency virus type 1 IQR interquartile range MSM men who have sex with men OL open‐label OLE open‐label extension (study) PC placebo‐controlled RAI receptive anal intercourse RCT randomized controlled trial RNA ribonucleic acid SAE serious adverse event STI sexually transmitted infection TDF tenofovir disoproxil fumarate TFV tenofovir URAI unprotected receptive anal intercourse WDAE withdrawal due to adverse event

iii

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

EXECUTIVE SUMMARY

Introduction Human immunodeficiency virus (HIV) attacks CD4+ T cells, components of the immune system necessary for defending the body against infection, and, if left untreated, may lead to acquired immunodeficiency syndrome (AIDS). Despite the wide availability and effectiveness of condoms in reducing sexual transmission, significant numbers of new HIV infections occur annually. The Public Health Agency of Canada estimates that 2,570 new infections (range: 1,940 to 3,200) occurred in Canada in 2014, with an estimated incidence rate of 7.2 per 100,000 population (range 5.5 to 9.0 per 100,000 population).1 There were approximately 1,396 new infections in 2014 in men who have sex with men (MSM), representing 54.3% of all new infections.2 Current HIV prevention strategies focus on behaviour change, and include education about sexual health and safer sex, reducing substance use or promoting safer substance use, and encouraging those at risk to get properly tested and diagnosed. Pre‐exposure prophylaxis (PrEP) for HIV is the use of drug therapy by HIV‐negative individuals to reduce their risk of acquiring HIV infection. Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) 200 mg/300 mg is a fixed‐ dose combination (FDC) tablet containing emtricitabine, a nucleoside HIV type 1 (HIV‐1) reverse transcriptase inhibitor, and tenofovir disoproxil fumarate, the prodrug of tenofovir, a nucleotide analogue reverse transcriptase inhibitor. FTC/TDF is the only antiretroviral therapy indicated for PrEP in adults at high risk of acquiring HIV‐1 infection. FTC/TDF is also indicated for use in combination with other antiretroviral drugs for the treatment of HIV‐1 infection in adults; however, this indication is not the focus of this review.

Indication under review For use in combination with safer sex practices for pre‐exposure prophylaxis to reduce the risk of sexually acquired HIV‐1 infection in adults at high risk.

Listing criteria requested by sponsor

As per indication.

The objective of this review is to perform a systematic review of the beneficial and harmful effects of FTC/TDF 200 mg/300 mg, once daily, in combination with safer sex practices for PrEP to reduce the risk of sexually acquired HIV‐1 infection in adults at high risk.

Results and Interpretation Included Studies Three double‐blind (DB), placebo‐controlled, randomized controlled trials (RCTs) assessing the safety and efficacy of once‐daily FTC/TDF 200 mg/300 mg as PrEP in combination with HIV prevention services for adults at high risk of acquiring HIV‐1 infection met the inclusion criteria for this review. All studies randomized participants in a 1:1 ratio to FTC/TDF or placebo. The iPrEx study (N = 2,499) was an international study conducted in adult MSM that continued until at least 85 seroconversion events occurred. The Partners PrEP study (N = 4,758) was conducted in adult Kenyan and Ugandan sexually active, serodiscordant, heterosexual couples who were followed for two to three years. The Centres for Disease Control’s (CDC’s) TDF2 study (N = 1,219) was conducted in Botswanan heterosexual men and women between 18 and 39 years who were sexually active; the study duration was planned for four years. The CDC TDF2 study was concluded early due to the lower‐than‐expected rate of retention of participants. In all three studies, study visits were scheduled every four weeks and included drug

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA dispensing, rapid blood testing for HIV‐1 antibodies, adherence counselling, risk‐reduction counselling, condom promotion, and treatment of symptomatic sexually transmitted infections (STIs) for all patients regardless of treatment group. In all studies, the primary end point was the incidence of HIV‐1 infections based on rapid testing at each monthly visit using pre‐specified testing algorithms. Other end points evaluated included sexual behaviour, the incidence of STIs, adherence to study drug, and HIV‐1 drug resistance in seroconversion participants.

One of the main limitations of the included studies was the generalizability of results, due to the enrolled population. The iPrEx study enrolled MSM who were at very high risk of acquiring HIV‐1 infection; the Partners PrEP study included serodiscordant couples in which the HIV‐1–positive partner was not to be taking antiretroviral therapy (ART); and the majority of enrolled participants were from Hispanic (iPrEx) or African countries (Partners PrEP and CDC TDF2). As such, the characteristics of the patients enrolled in these trials may not reflect the full spectrum of patients who would be seen in the Canadian setting. Measures of treatment adherence were based on pill count and patient self‐report, and may therefore have been subject to bias. As no adjustments for multiple testing were performed for secondary end points, results need to be interpreted with caution due to the potential for type I error. Although quality of life was cited as an important outcome according to the patient groups who provided input for this submission, health‐related quality of life was not measured in any of the included studies.

Efficacy In the iPrEx study, participants had been followed for a median of 1.2 years (range 1 day to 2.8 years) at the time of the primary data analysis. In the Partners PrEP study, HIV‐1–negative partners were followed for a median of 23 months (range: one to 36 months). In the CDC TDF2 study, participants were followed for a median of 1.1 years (maximum: 3.7 years) before the study was concluded.

The incidence of HIV‐1 seroconversion was the primary efficacy end point in all studies. Paired rapid HIV tests were administered at each monthly visit, and discordant or positive results were retested or confirmed using rigorous testing algorithms. In the primary efficacy analysis, participants determined to be HIV‐positive at baseline were excluded. In all studies, there was a statistically significant reduction in the incidence of HIV‐1 seroconversion with FTC/TDF compared with placebo. In the iPrEx study, there was a relative risk reduction of 44% (95% confidence interval [CI], 15% to 63%; P = 0.005) in HIV‐1 seroconversion with FTC/TDF versus placebo. vv vvv vvvvv vvvvvv vvv vvv vvvvvvvvvvvv vvvvvvv vvvv vvvvvvv vvv vvv vvvvv v vvvv vv vvv vvvvvvvvvvvvvvv vvvv vv vvv vv vvvv vvvvv vv vvvvvvvvv vvvvvvvv vv vvvvv vv vvvvvvv. In the Partners PrEP study, there was a relative risk reduction of 75% (95% CI, 55% to 87%; P < 0.001) in HIV‐1 seroconversion with FTC/TDF versus placebo. vv vvv vvvvvvvvv vvvv vvvvvv vvv vvv vvvvvvvvvvvv vvvvvvv vvvv vvvvvvv vvv vvv vvvvv v vvvv vv vvv vvvvvvvvvvvvvvv vvvv vv vvv vv vvvv vvvvv vv vvvvvvvvv vvvvvvvv vv vvvvv vv vvvvvvv. In the CDC TDF2 study, there was a relative risk reduction of 62.2% (95% CI, 21.5% to 83.4%; P = 0.03) in HIV‐1 seroconversion with FTC/TDF versus placebo.

In all studies, an analysis of drug level detection in all HIV‐1 seroconversion cases and matched controls (participants who did not seroconvert) was performed. All studies examined plasma levels of the drug components, and the iPrEx study also looked at intracellular drug levels. In the iPrEx study, there was detectable plasma FTC and tenofovir (TFV) in 6% of HIV‐1 seroconversion participants compared with vvvvv of control participants. In the Partners PrEP study, there was detectable plasma TFV (FTC levels were not evaluated) in vvvvv of HIV‐1 seroconversion participants compared with vvvvv of control

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA participants. In the CDC TDF2 study, there was detectable plasma FTC and TFV in 50% of HIV‐1 seroconversion participants compared with approximately 80% of control participants.

In the iPrEx study, the mean and median rate of self‐reported pill use was similar between the FTC/TDF and placebo groups (mean: 88.7% versus vvvvv; median: vvvvv for both groups). In the Partners PrEP study, study drug adherence was assessed using pill counts from returned study bottles; more than 98% of dispensed study bottles were returned, and 94% of dispensed study tablets were taken across treatment groups. In the CDC TDF2 study, rates of adherence were estimated to be similar across treatment groups according to pill counts (FTC/TDF 84.1% versus placebo 83.7%), and self‐reported adherence for the preceding three days (FTC/TDF 94.4% versus placebo 94.1%). In the Partners PrEP study, an adherence sub‐study (N = 1,147) was conducted, in which unannounced, home‐based pill counts were conducted monthly for the first six months and then quarterly. Results from this sub‐study suggested that adherence was high in the Partners PrEP study across treatment groups (mean: 98%) and corroborated by the results from self‐report and pill counts in the full study. No adherence sub‐studies were conducted in the iPrEx and CDC TDF2 study.

In addition to daily FTC/TDF or placebo, participants were given risk‐reduction counselling at each monthly visit and were connected with existing local prevention services when required in the studies. Overall, no differences in sexual behaviour were seen between the FTC/TDF and placebo groups across studies. In the iPrEx study, the number of receptive anal intercourse (RAI) partners in the past 12 weeks decreased during the study from a mean of approximately 12 partners to a mean of fewer than five partners, and the percentage of those partners who used a condom increased from 50% to more than 70%. In the Partners PrEP study at enrolment, 27% of HIV‐1–negative participants reported having had sex without a condom during the previous month. This percentage decreased during the follow‐up period to 13% and 9% at 12 and 24 months, respectively, and this was similar between treatment groups. In the CDC TDF2 study, the percentage of sexual episodes using condoms with the main or most recent sexual partner was 81.4% (range: 76.6% to 86.4%) in the FTC/TDF group and 79.2% (range: 71.6% to 87.6%) in the placebo group at baseline, and remained similar between groups and stable over 24 weeks. The number of sexual partners in the previous month was similar between treatment groups throughout the study and declined slightly over time (P < 0.001 for trend; P = 0.95 between treatment groups). Because sexual risk behaviour was self‐reported, results may be biased by social desirability and the incidence of STIs may be a more objective measure of sexual behaviour. However, the proportion of participants with STIs over time was not reported in any of the included studies, although the incidence of STIs was similar between the FTC/TDF and placebo groups.

In the patient input group submission, participants expressed that FTC/TDF PrEP would alleviate their anxiety and fear of becoming HIV‐positive after engaging in risky sexual behaviour, whether it be condomless sex or sex with HIV‐1–positive partners. However, health‐related quality of life was not assessed in any of the included studies.

Harms Overall, the incidence of adverse events (AEs) was similar across the FTC/TDF and placebo groups in the iPrEx study (69% versus 70%), the Partners PrEP study (86% versus 85%), and the CDC TDF2 study (91% versus 88%). Common AEs among the three studies included upper respiratory tract infection, pharyngitis, diarrhea, and headache. In the CDC TDF2 study, common AEs also included abdominal pain, dizziness, nausea, vomiting, and weight loss. The incidence of AEs was similar across the FTC/TDF and placebo groups in the iPrEx study (5% for both groups), the Partners PrEP study (7% for both groups), and the CDC TDF2 study (7% for both groups). In the iPrEx study, 2% of patients withdrew due to an vi

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA adverse event in both treatment groups. In the iPrEx study, there was no pattern of AEs that led to discontinuation. In the Partners PrEP study, two participants in the FTC/TDF group and one participant in the placebo group withdrew due to an adverse event. In the Partners PrEP study, all discontinuations were due to an increase in blood creatinine level that was confirmed on repeat testing. In the CDC TDF2 study, no participants withdrew from the study due to an AE. In the iPrEx study, one patient in the FTC/TDF group and four patients in the placebo group died. In the Partners PrEP study, eight patients in the FTC/TDF group and nine patients in the placebo group died. In the CDC TDF2 study, two patients in the FTC/TDF group and four patients in the placebo group died.

Notable harms associated with FTC/TDF include renal AEs and bone AEs. In the included studies, the incidence of elevated creatinine levels (defined as 1.5 times baseline level) did not exceed 2% in any group across studies, and the incidence of bone ‐fracture AEs did not exceed 1% across studies, with the majority of bone fractures being trauma‐related. The Health Canada product monograph recommends that FTC/TDF for PrEP should not be used in HIV‐1–uninfected individuals with creatinine clearance below 60 mL/min, which corresponds to the participants enrolled in the iPrEx and Partners PrEP studies.

The Health Canada product monograph recommends that FTC/TDF for PrEP be used as part of a comprehensive prevention strategy that includes safer sex practices, patients’ knowledge of their HIV‐1 status and the status of their partner(s), and regular testing for STIs. In the included studies, follow‐up visits were conducted monthly, and included HIV testing, risk‐reduction counselling, adherence counselling, treatment of symptomatic STIs, and provision of condoms and contraceptives. According to the clinical expert consulted by the CADTH Common Drug Review (CDR) for this review, participants on PrEP therapy would not likely be seen as frequently in clinical practice, and follow‐up visits would likely be conducted every three months. According to the Health Canada product monograph, the use of FTC/TDF 200 mg/300 mg for PrEP must be prescribed only to individuals confirmed to be HIV‐negative immediately prior to initial use and periodically (at least every three months) during use.

Conclusions Three DB, placebo‐controlled RCTs assessing the safety and efficacy of once‐daily FTC/TDF 200 mg/300 mg as PrEP in combination with HIV prevention services for individuals at high risk of acquiring HIV‐1 infection were included in this review. The iPrEx study was conducted in adult MSM, the Partners PrEP study was conducted in adult Kenyan and Ugandan sexually active, serodiscordant, heterosexual couples, and the CDC TDF2 study was conducted in young Botswanan heterosexual men and women. Results from all studies suggested that there was a statistically significant reduction in the incidence of HIV‐1 seroconversion with FTC/TDF compared with placebo. Treatment adherence based on pill count and self‐report was high across studies, but may be subject to bias. Sexual behaviour and the incidence of STIs did not differ between the FTC/TDF and placebo groups and small improvements were seen over time, although the reliance on participant interviews may also be vulnerable to bias. Although quality of life was cited as an important outcome according to patient‐group input, this was not evaluated in the included studies. Overall, the incidence of AEs was similar between FTC/TDF and placebo groups, and the incidence of renal and bone AEs were low across studies. None of the studies were conducted in Canada, and there may be generalizability issues, as the included studies were conducted mainly in Hispanic and African countries where health care services may not be as accessible as they are in the Canadian setting.

vii

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

TABLE 1: SUMMARY OF RESULTS iPrEx Partners PrEP CDC TDF2 FTC/TDF Placebo FTC/TDF Placebo FTC/TDF Placebo HIV‐1 seroconversion (mITT set) (n = 1,224) (n = 1,217) (n = 1,576) (n = 1,578) (n = 601) (n = 599) Person‐years of follow‐up vvvv vvvv 2,616 2,607 1,563 Participants with seroconversion 36 64 13 52 9 24 events, n Rate per 100 person‐years 2.2 3.8 0.50 1.99 1.2 3.1 Hazard ratio (95% CI) 0.56 (0.37 to 0.85) 0.25 (0.13 to 0.45) NR Relative risk reduction, % (95% CI) 44 (15 to 63) 75 (55 to 87) 62.2 (21.5 to 83.4) P value 0.005 < 0.001 0.03 Absolute rate reduction, per 100 vvv vvvvv vvvv vvv vvvvv vvvv NR person‐years (95% CI)a Harms (safety set), n (%) (n = 1,251) (n = 1,248) (n = 1,579) (n = 1,584) (n = 611) (n = 608) Participants with > 0 AEs 867 (69) 877 (70) 1,362 (86) 1,350 (85) 557 (91) 536 (88) Participants with > 0 SAEs 60 (5) 67 (5) 115 (7) 118 (7) 115 (7) 118 (7) Participants with > 0 WDAEs 25 (2) 27 (2) 2 (< 1) 1 (< 1) 0 0 Number of deaths 1 (< 1) 4 (< 1) 8 (< 1) 9 (< 1) 2 (< 1) 4 (< 1) Notable harms (safety set), n (%) (n = 1,251) (n = 1,248) (n = 1,579) (n = 1,584) (n = 611) (n = 608) Elevated creatinineb 25 (2) 14 (1) 20 (1) 13 (1) 1 (< 1) 0 Bone fracture 15 (1) 11 (1) 9 (< 1) 13 (1) 7 (1) 6 (1)

AE = adverse event; CI = confidence interval; FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; HIV = human immunodeficiency virus; mITT = modified intent‐to‐treat; NR = not reported; SAE = serious adverse event; WDAE = withdrawal due to adverse event. a Provided by the manufacturer.3 b Defined as an increase in serum creatinine of at least 1.5 times the baseline value. Sources: iPrEx Clinical Study Report (CSR),4 Grant et al., 2010,5 Partners PrEP CSR,6 Baeten et al., 2012,7 Thigpen et al., 2012.8

viii

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

1. INTRODUCTION

1.1 Disease Prevalence and Incidence Human immunodeficiency virus (HIV) attacks CD4+ T cells, components of the immune system necessary for defending the body against infection.9 HIV progressively impairs immune response and, if left untreated, may lead to acquired immunodeficiency syndrome (AIDS), the final stage of HIV where a patient can no longer fight off infections and certain malignancies. HIV is transmitted through bodily fluids, and can be passed from an infected individual to a healthy individual through unprotected sex and the sharing of drug needles.10 An infected mother can also pass the virus to her baby during pregnancy or birth (vertical transmission) or breastfeeding. HIV can be divided into two major types, HIV type 1 (HIV‐1) and HIV type 2 (HIV‐2); HIV‐1 is the predominant virus worldwide.11

At the end of 2014, Health Canada estimated that 75,500 people were living with HIV infection in Canada.2 In spite of the fact that the sexual transmission of HIV is significantly reduced by the use of condoms, significant numbers of new HIV infections occur annually.12,13 The Public Health Agency of Canada estimates that 2,570 new infections (range: 1,940 to 3,200) occurred in Canada in 2014, with an estimated incidence rate of 7.2 per 100,000 population (range: 5.5 per 100,000 population to 9.0 per 100,000 population).1 There were approximately 1,396 new infections in 2014 in men who have sex with men (MSM), representing 54.3% of all new infections.2 This estimate is similar to the 2011 estimate of 1,416 new infections. According to 2011 national estimates, MSM have incidence rates 71 times higher than other men, people who inject drugs have incidence rates 46 times higher than people who do not inject drugs, and males have incidence rates 3.3 times higher than females.2 In 2011, approximately 95% of reported HIV/AIDS cases were from Ontario (42.6%); Quebec had 21.5% of cases, British Columbia 13.4%, Alberta 9.7%, and Saskatchewan 7.7%.14 Canadian estimates for the year 2011 demonstrated that the populations most affected by new HIV infections vary across provinces, with MSM being the most affected risk group in British Columbia, Ontario, Quebec, and the Atlantic provinces, heterosexual individuals being most affected risk group in Alberta and Manitoba, and injection drug users being the most affected risk group in Saskatchewan.2 The rising rates of gonorrhea, chlamydia, and syphilis in Canada serve to emphasize the inconsistency of condom use among sexually active populations.15

1.2 Standards of Therapy The current standard of care for HIV management is to treat with highly active antiretroviral therapy (ART), with the primary goal of achieving and maintaining maximal suppression of viral load, which leads to restoration and preservation of immunologic function, improvement of quality of life, and reduction of HIV‐related morbidity and mortality.16 HIV‐infected patients require ART for life, resulting in a heavy economic burden and high health care utilization. Reducing the number of additional HIV infections is an important step to alleviating this burden.

Current HIV prevention strategies focus on, among others, behaviour change (including education about sexual health and safer sex), reducing substance use or promoting safer substance use, and encouraging those at risk to get properly tested and diagnosed.17 Despite the wide availability of sexual health resources in Canada, the incidence of HIV is not declining.2

Pre‐exposure prophylaxis (PrEP) for HIV is the use of drug therapy, typically antiretrovirals, by HIV‐ negative individuals to reduce their risk of acquiring HIV infection.18 Currently, Truvada (emtricitabine/tenofovir disoproxil fumarate [FTC/TDF]) 200 mg/300 mg is the only drug approved for this indication. Truvada was first approved by the US Food and Drug Administration (FDA) in 2012 for

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

HIV PrEP, and received a Notice of Compliance from Health Canada on February 23, 2016. The Centres for Disease Control and Prevention (CDC) and the World Health Organization (WHO) recommend the daily use of Truvada as a prevention option for sexually active MSM, sexually active adult heterosexual men and women, and adult intravenous drug users at substantial risk of HIV acquisition, to be used within a comprehensive HIV prevention package.19,20

1.3 Drug FTC/TDF is a fixed‐dose combination (FDC) tablet containing emtricitabine, a nucleoside HIV‐1 reverse transcriptase inhibitor, and tenofovir disoproxil fumarate, the prodrug of tenofovir, a nucleotide analogue reverse transcriptase inhibitor. FTC/TDF is available as FDC tablets containing 200 mg FTC and 300 mg TDF. The Health Canada–recommended dose is one tablet taken orally once daily.

FTC/TDF is indicated in combination with other antiretroviral agents for the treatment of HIV‐1 infection in adults. This indication has previously been reviewed by the CADTH Common Drug Review (CDR) and received a recommendation to “list with criteria” (see the Canadian Expert Drug Advisory Committee’s [CEDAC’s] final recommendation, December 17, 2008).21

FTC/TDF is also indicated in combination with safer sex practices for PrEP to reduce the risk of sexually acquired HIV‐1 infection in adults at high risk. This indication will be the focus of this review.

Indication under review

For use in combination with safer sex practices for pre‐exposure prophylaxis to reduce the risk of sexually acquired HIV‐1 infection in adults at high risk.

Listing criteria requested by sponsor

As per indication.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

2. OBJECTIVES AND METHODS

2.1 Objectives To perform a systematic review of the beneficial and harmful effects FTC/TDF 200 mg/300 mg in combination with safer sex practices for PrEP to reduce the risk of sexually acquired HIV‐1 infection in adults at high risk.

2.2 Methods All manufacturer‐provided trials considered pivotal by Health Canada were included in the systematic review. Phase 3 studies were selected for inclusion based on the selection criteria presented in Table 2.

TABLE 2: INCLUSION CRITERIA FOR THE SYSTEMATIC REVIEW Patient Population Adults at high riska of HIV‐1 infection. Subgroups of interest: Sex (female or male) Intervention FTC/TDF 200 mg/300 mg (FDC) in combination with safer sex practices Comparators Placebo, in combination with safer sex practices Outcomes Key efficacy outcomes: b  HIV‐1 seroconversion b  Sexual behaviour  Incidence of STIs (e.g., chlamydia, gonorrhea, syphilis, herpes)

Other efficacy outcomes:  Adherence and persistence to study medication b  Quality of life as measured by a validated scale  HIV‐1 drug resistance

Harms outcomes:  AEs, SAEs, WDAEs, mortality  Notable harms: renal impairment, bone AEs Study Design Published and unpublished phase 3 RCTs

AE = adverse event; FDC = fixed‐dose combination; FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; HIV‐1 = human immunodeficiency virus type 1; RCT = randomized controlled trial; SAE = serious adverse event; STI = sexually transmitted infection; WDAE = withdrawal due to adverse event. a Factors that may identify individuals at high risk: “has partner(s) known to be HIV‐1–infected, or engages in sexual activity within a high prevalence area or social network and one or more of the following: inconsistent or no condom use, diagnosis of STIs, exchange of sex for commodities (such as money, food, shelter, or drugs), use of illicit drugs or alcohol dependence, incarceration, partner(s) of unknown HIV‐1 status with any of the factors listed above.” (Source: Health Canada product monograph.22) b Outcomes identified by patients as important in patient‐group submission.

The literature search was performed by an information specialist using a peer‐reviewed search strategy.

Published literature was identified by searching the following bibliographic databases: MEDLINE (1946–) with in‐process records and daily updates via Ovid; Embase (1974–) via Ovid; and PubMed. The search strategy consisted of both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Truvada (emtricitabine/tenofovir) and pre‐exposure prophylaxis.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

Methodological filters were applied to limit retrieval to randomized controlled trials. Where possible, retrieval was limited to the human population. Retrieval was not limited by publication year or by language. Conference abstracts were excluded from the search results. See Appendix 2 for the detailed search strategies.

The initial search was completed on March 31, 2016. Regular alerts were established to update the search until the meeting of the CADTH Canadian Drug Expert Committee (CDEC) on July 20, 2016. Regular search updates were performed on databases that do not provide alert services.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the following sections of the Grey Matters checklist (https://www.cadth.ca/grey‐ matters): Health Technology Assessment Agencies; Health Economics; Clinical Practice Guidelines; Drug and Device Regulatory Approvals; Advisories and Warnings; Drug Class Reviews; Databases (free). Google and other Internet search engines were used to search for additional Web‐based materials. These searches were supplemented by reviewing the bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

Two CDR clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full‐text articles of all citations considered potentially relevant by at least one reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion. Included studies are presented in Table 3; excluded studies (with reasons) are presented in 0.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

3. RESULTS

3.1 Findings From the Literature A total of 230 studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 3, Table 4 and Table 5 and described in section 3.2 Included Studies. A list of excluded studies is presented in APPENDIX 3: EXCLUDED STUDIES.

FIGURE 1: FLOW DIAGRAM FOR INCLUSION AND EXCLUSION OF STUDIES

230 Citations identified in literature search

5 15 Potentially relevant reports Potentially relevant reports from other sources identified and screened

20 Total potentially relevant reports identified and screened

6 Reports excluded

14 Reports included Presenting data from 3 unique studies

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

TABLE 3: DETAILS OF THE IPREX STUDY (MEN WHO HAVE SEX WITH MEN) iPrEx (CO‐US‐104‐0288) Study Design DB, PC, RCT Locations 11 centres in 6 countries: Brazil, Ecuador, Peru, South Africa, Thailand, US Randomized (N) 2,499 Inclusion Criteria ‒ HIV‐1–negative males ≥ 18 years with evidence of high risk for acquiring HIV‐1 infection based on sexual encounters with males in the past 6 months and meeting

one of the following criteria: no condom use during anal intercourse with an HIV‐ positive partner or partner of unknown HIV‐1 status; anal intercourse with > 3 partners; exchanged money, gifts, shelter, or drugs for anal sex; had sex with partner

OPULATIONS and was diagnosed with an STI. P

& ‒ Adequate renal function (creatinine clearance ≥ 60 mL/min), hepatic function (ALT and AST ≤ 2 x ULN, bilirubin ≤ 1.5 mg/dL), and hematologic function (neutrophils ≥ 1,500/mm3, platelets > 150,000/mm3, hemoglobin ≥ 10 g/dL) within 28 days of ESIGNS

D enrolment. Exclusion Criteria ‒ Previously diagnosed active and serious infections (e.g., tuberculosis) ‒ Acute hepatitis B infection ‒ History of pathological bone fractures ‒ Receiving or had received antiretroviral therapies ‒ Active alcohol or drug use considered sufficient to hinder compliance Intervention FTC/TDF 200 mg/300 mg FDC taken orally once daily: ‒ Given with a comprehensive package of infection prevention services (HIV testing,

risk‐reduction counselling, condoms, diagnosis and treatment for symptomatic STIs)

RUGS ‒ Participants were connected with local prevention and treatment services when D required Comparator(s) ‒ Placebo given with a comprehensive package of infection prevention services

Duration Study continued until 85 seroconversion events were identified ‒ Study visits scheduled every 4 weeks ‒ High‐risk behaviours assessed every 12 weeks URATION

D ‒ Evaluations for STIs performed every 24 weeks Primary End Point Incidence of HIV‐1 seroconversion Other End Points ‒ HIV‐1 drug resistance in seroconverted participants ‒ Adherence (self‐reported, clinic pill counts)

UTCOMES ‒ Sexual behaviour (number of partners in past 3 months, proportion of partners with O whom condoms were used in past 3 months) ‒ STIs Publications Grant et al., 20105

Other publications: 23

OTES ‒ Deutsch et al., 2015 N ‒ Marcus et al., 201324 ‒ Solomon et al., 201425

ALT = alanine aminotransferase; ART = antiretroviral therapy; AST = aspartate aminotransferase; DB = double‐blind; FDC = fixed‐dose combination; FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; HIV‐1 = human immunodeficiency virus type 1; PC = placebo‐controlled; RCT = randomized controlled trial; RNA = ribonucleic acid; STI = sexually transmitted infection; ULN = upper limit of normal. Note: Three additional reports were included (manufacturer’s submission,26 Health Canada’s Reviewers Report,27 and US Food and Drug Administration [FDA] Medical Review28). 4 5 Sources: iPrEx Clinical Study Report, Grant et al., 2010.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

TABLE 4: DETAILS OF THE PARTNERS PREP STUDY (HETEROSEXUAL SERODISCORDANT COUPLES)

Partners PrEP (CO‐US‐104‐0380) Study Design DB, PC, RCT Locations 9 centres in 2 countries: Kenya, Uganda Randomized (N) 4,758 couples Inclusion Criteria Heterosexual HIV‐1–serodiscordant couples who are sexually active (vaginal intercourse ≥ 6 times in previous 3 months) and planned to remain in the relationship for the duration of the study period. HIV‐1–negative partner  Between 18 and 65 years old  Adequate renal function (creatinine clearance ≥ 60 mL/min), hepatic function (ALT and AST ≤ 2 x ULN, bilirubin ≤ 1.5 x ULN), and hematologic function (neutrophils ≥ 1,300/mm3, platelets > 125,000/mm3, hemoglobin ≥ 11 g/dL) within 56 days of enrolment.

OPULATIONS HIV‐1–positive partner P

&  HIV‐1 infection based on positive enzyme immunoassay  CD4 cell count ≥ 250 cells/mm3 not meeting national guidelines for initiation of

ESIGNS ART D Exclusion Criteria HIV‐1–negative partner  Previously diagnosed active and serious infections (e.g., tuberculosis)  Acute hepatitis B infection  History of pathological bone fractures  Receiving or had received ART  vvvvvv vvvvvvv vv vvvv vvv vvvvvvvvvv vvvvvvvvvv vv vvvvvv vvvvvvvvvv  Current pregnancy or breastfeeding HIV‐1–positive partner  Current use of ART Intervention HIV‐1–negative partner  FTC/TDF 200 mg/300 mg FDC taken orally once daily TDF 300 mg taken orally once daily

RUGS  to be given with HIV risk‐reduction counselling D Comparator(s) Placebo  to be given with HIV risk‐reduction counselling

Duration Participants were followed for 24 to 36 months to generate a sufficient accumulation of person‐years to adequately evaluate study end points

URATION  Study visits scheduled every 4 weeks D Primary End Point Incidence of HIV‐1 seroconversion

Other End Points  HIV‐1 drug resistance in seroconverted participants  Adherence (clinic pill counts)

UTCOMES  Sexual behaviour (proportion of participants reporting having unprotected sex O with HIV‐1–positive partner in the past month)  STIs

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

Partners PrEP (CO‐US‐104‐0380) Publications Baeten et al., 20127

Other publications:

OTES 29

N  Mugwanya et al., 2015  Mujugira et al., 201130

ALT = alanine amino transferase; ART = antiretroviral therapy; AST = aspartate aminotransferase; DB = double‐blind; FDC = fixed‐dose combination; FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; HIV‐1 = human immunodeficiency virus type 1; PC = placebo‐controlled; MSM = men who have sex with men; RCT = randomized controlled trial; RNA = ribonucleic acid; STI = sexually transmitted infection; TDF = tenofovir disoproxil fumarate; ULN = upper limit of normal. Note: Three additional reports were included (manufacturer’s submission,26 Health Canada Reviewers’ Report,27 and US Food and Drug Administration [FDA] Medical Review28). Sources: Partners PrEP Clinical Study Report,6 Baeten et al., 2012.7

TABLE 5: DETAILS OF THE CDC TDF2 STUDY (HETEROSEXUAL MEN AND WOMEN) CDC TDF2 Study Design DB, PC, RCT Locations 2 centres in Botswana

Randomized (N) 1,219 men and women Inclusion Criteria  HIV‐1–negative heterosexual adults between 18 and 39 years old who are sexually active (≥ 1 partner in past 3 months)  Adequate renal function (creatinine clearance ≥ 60 mL/min), hepatic function (ALT OPULATIONS P

and AST ≤ 2 x ULN, bilirubin ≤ 1.5 x ULN), and hematologic function (hemoglobin ≥ 8

& g/dL) within 30 days of enrolment  Female participants willing to use effective contraception during study

ESIGNS Exclusion Criteria  Chronic illness requiring ongoing prescription medication D  History of significant renal or bone disease  Current pregnancy or breastfeeding  Planning to move from trial community within 12 months Intervention FTC/TDF 200 mg/300 mg FDC taken orally once daily

 to be given with HIV risk‐reduction counselling

RUGS Comparator(s) Placebo D  to be given with HIV risk‐reduction counselling

Duration Planned 4 years of treatment, with HIV‐1–uninfected participants remaining on assigned medication until the last enrolled participant has completed 12 months or closure of the study URATION

D  Study visits scheduled every 4 weeks Primary End Point Incidence of HIV‐1 seroconversion

Other End Points  Adherence (self‐reported, clinic pill counts)  Sexual behaviour (number of sexual partners in previous month, percentage of UTCOMES

O sexual episodes using condoms with most recent sexual partner)  HIV‐1 drug resistance in seroconverted participants Publications Thigpen et al., 20128 8

OTES Bone mineral density sub‐study: Kasonde et al., 2014 N

ALT = alanine amino transferase; ART = antiretroviral therapy; AST = aspartate aminotransferase; DB = double‐blind; FDC = fixed‐dose combination; FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; HIV‐1 = human immunodeficiency virus type 1; PC = placebo‐controlled; RCT = randomized controlled trial; RNA = ribonucleic acid; STI = sexually transmitted infection; ULN = upper limit of normal. Note: One additional report was included (manufacturer’s submission26). Source: Thigpen et al., 2012.8

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

3.2 Included Studies 3.2.1 Description of Studies All three included studies were randomized controlled trials (RCTs), double‐blind (DB), placebo‐ controlled studies that assessed the safety and efficacy of PrEP of oral FTC/TDF 200 mg/300 mg in combination with HIV prevention services. The manufacturer was responsible for providing the study drug, but was not involved in the design and conduct of the studies. Randomization was stratified by study site.

The Pre‐exposure Prophylaxis Initiative study (iPrEx, N = 2,499) was an international study conducted in adult seronegative MSM who were at high risk of acquiring HIV‐1 infection. Study duration was event driven, continuing until at least 85 seroconversion events occurred. The first participant was screened on July 10, 2007, and the last participant observation for the primary study analysis was performed on May 1, 2010. Cumulative safety and efficacy data from study visits through November 21, 2010 were also available. The primary sponsor for the iPrEx study was the US National Institutes of Health.

The Partners PrEP study (N = 4,758) was conducted in Kenyan and Ugandan adult heterosexual serodiscordant couples in which one partner had HIV type 1 (HIV‐1) infection while the other partner did not, and in which the couple was sexually active with plans to remain in the relationship for the duration of the study period. In the Partners PrEP study, enrolled participants were planned to be followed for a minimum of 24 months up to a maximum of 36 months, and the follow‐up schedule was designed to yield a sufficient accumulation of person‐years to adequately evaluate the study end points. The first participant was screened on June 19, 2008, and the last participant observation occurred on July 10, 2011. The placebo group was discontinued after this date because predetermined stopping rules were met. The primary sponsor for the Partners PrEP study was the University of Washington.

The CDC TDF2 study (N = 1,219) was conducted in Botswanan heterosexual men and women who were sexually active. In the CDC TDF2 study, four years of treatment were planned, with HIV‐1–uninfected participants to remain on assigned medication until the last enrolled participant had completed 12 months of treatment. The first participant was enrolled on March 22, 2007. A lower‐than‐expected rate of retention was observed during this study due to relocation of participants, and revised sample size calculations indicated that the study would need to expand enrolment. Due to the logistical challenges of doing so, the study was concluded early and all participants exited the study by May 31, 2010. The primary sponsor for the CDC TDF2 study was the US Centers for Disease Control and Prevention (CDC).

In all studies, study visits were scheduled every four weeks and included drug dispensing, rapid testing for HIV‐1 antibodies, adherence counselling, risk‐reduction counselling, condom promotion, and treatment of symptomatic sexually transmitted infections (STIs). HIV‐1–uninfected women were also tested for pregnancy, and women who became pregnant stopped using the study drug.

3.2.2 Populations a) Inclusion and exclusion criteria Each of the three included studies focused on a different population at risk of acquiring HIV‐1 infection, with inclusion criteria to reflect this. The iPrEx study included males at least 18 years of age with sexual encounters with men in the past six months meeting one of the following criteria: no condom use during anal intercourse, anal intercourse with more than three partners, diagnosis of an STI after a sexual encounter, or having transactional anal sex. The Partners PrEP study included heterosexual HIV‐1– serodiscordant couples who were sexually active based on having had vaginal intercourse at least six times in the previous three months, with the HIV‐1–negative partner being between 18 and 65 years of 9

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA age. The CDC TDF2 study included heterosexual males and females between 18 and 39 years of age who had had at least one sexual partner in the past three months. In all studies, participants were to have adequate renal, hepatic, and hematologic function. Exclusion criteria included a history of significant renal or bone disease, previous or current use of antiretroviral therapies, or issues that would hinder compliance or follow‐up of the participant.

Participants who were not immune to hepatitis B virus were offered vaccination. Those who were not immune and who declined vaccination were tested for the virus annually and at the stop visit. Females who were pregnant or breastfeeding were excluded in the Partners PrEP and CDC TDF2 studies, and contraception was to be used upon enrolment. Women who became pregnant during the study were to be withdrawn from study drug. In the Partners PrEP study, women whose pregnancies did not go to term or that ended in stillbirth were permitted to resume the study drug after confirmation by a negative urine pregnancy test. b) Baseline characteristics Baseline characteristics were generally balanced across the FTC/TDF and placebo groups in all of the studies. In the iPrEx study, the mean age was 27 years, and 14% of the male‐at‐birth population identified themselves as transgender women. The largest proportion of patients (approximately 50%) was between 18 and 24 years of age, and more than 70% of the population was Hispanic. At screening, participants reported a mean of 18 sexual partners in the previous 12 weeks, with approximately 60% of participants having engaged in unprotected receptive anal intercourse (URAI) during that time. STIs were generally balanced across groups, with approximately one‐third of participants testing positive for herpes simplex virus, gonorrhea, and chlamydia.

In the Partners PrEP study, the majority of HIV‐1–negative partners were male (61% to 64%), and the mean age was approximately 33 years. Almost all of the enrolled couples were married (98%), and the mean number of years aware of the discordant status was 0.4 years. For the HIV‐1–positive partners, the mean HIV‐1 plasma ribonucleic acid (RNA) level was 3.9 log10 copies/mL and the mean CD4+ cell count was 498/mm3. The proportion of participants with curable STIs was low, and ranged between 6% and 9% across groups.

In the CDC TDF2 study, approximately 54% of participants were male, and the majority of participants (87.5% to 90%) were between 21 and 29 years of age. More than 90% of participants were single, and 88% of participants had had at least one sexual partner in the previous month. The percentage of sexual episodes in which condoms had been used with the main or most recent partner was 80%, and 3.5% of participants had had sex with a known HIV‐positive partner in the previous month. More than 30% of participants were seropositive for herpes simplex virus.

TABLE 6: SUMMARY OF BASELINE CHARACTERISTICS OF IPREX STUDY (MSM) Characteristic iPrEx FTC/TDF Placebo (n = 1,251) (n = 1,248) Age, mean years vvvv vvvv Transgender women, n (%) 339 (14) Age, n (%) 18 to 24 years 591 (47) 662 (53) 25 to 29 years 274 (22) 241 (19)

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

Characteristic iPrEx FTC/TDF Placebo (n = 1,251) (n = 1,248) 30 to 39 years 249 (20) 224 (18) ≥ 40 years 137 (11) 121 (10) Race, n (%) Black/African‐American 117 (9) 97 (8) White 223 (18) 208 (17) Mixed/Other 849 (68) 878 (70) Asian 62 (5) 65 (5) Hispanic 900 (72) 906 (73) Education Level, n (%) Less than secondary 279 (22) 244 (20) Completed secondary 430 (34) 453 (36) Post‐secondary 525 (42) 539 (43) Number of alcoholic drinks on days when alcohol was consumed in the past month, n (%) 0 206 (16) 184 (15) 1 to 4 per day 348 (28) 345 (28) ≥ 5 per day 666 (53) 687 (55) Sexual risk factors at screening Mean (SD) number of partners in previous 12 weeks 18 (35) 18 (43) URAI in previous 12 weeks, n (%) 732 (59) 753 (60) URAI with HIV+ or unknown status partner in previous 992 (79) 1,009 (81) 6 months, n (%) Transactional sex in previous 6 months, n (%) 517 (41) 510 (41) Known HIV+ partner in previous 6 months, n (%) 23 (2) 32 (3) STI diagnosed at screening Syphilis seroreactivity, n/n tested (%) 164/1240 (13) 162/1239 (13) Serum HSV‐2 infection, n/n tested (%) 458/1241 (37) 430/1243 (35) Gonorrhea PCR positive, n/n tested (%) 7/20 (35) 5/22 (23) Chlamydia PCR positive, n/n tested (%) 8/20 (40) 8/22 (36) HBV status Susceptible 827 (66) 803 (64) Immune due to natural infection 247 (20) 222 (18) Immune due to prior vaccination 149 (12) 190 (15) Current infection 7 (1) 6 (0) Indeterminate 21 (2) 27 (2)

FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; HBV = hepatitis B virus; HIV = human immunodeficiency virus; HSV = herpes simplex virus; MSM = men who have sex with men; PCR = polymerase chain reaction; SD = standard deviation; STI = sexually transmitted infection; URAI = unprotected receptive anal intercourse. Sources: iPrEx Clinical Study Report,4 Grant et al., 2010,5 Deutsch et al., 2015,23 and US Food and Drug Administration (FDA) Medical Review.28

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

TABLE 7: SUMMARY OF BASELINE CHARACTERISTICS OF PARTNERS PREP STUDY (SERODISCORDANT HETEROSEXUAL COUPLES) Characteristic Partners PrEP FTC/TDF Placebo (n = 1,579) (n = 1,584) Seronegative Seropositive Seronegative Seropositive partner partner partner partner Age, median (IQR) years vv vvvv vvv vv vvvv vvv vv vvvv vvv vv vvvv vvv Age, n (%) 18 to 24 years 177 (11) 287 (18) 172 (11) 273 (17) 25 to 34 years 690 (44) 636 (40) 688 (43) 629 (40) 35 to 44 years 498 (32) 460 (29) 513 (32) 509 (32) ≥ 45 years 214 (14) 196 (12) 211 (13) 173 (11) Male, n (%) 1,013 (64) 566 (36) 963 (61) 621 (39) Female, n (%) 566 (36) 1,013 (64) 621 (39) 963 (61) Education, median (IQR) years 7 (4 to 10) 7 (4 to 9) 7 (4 to 10) 7 (4 to 9) Any monthly income, n (%) 1,236 (78) 1,052 (67) 1,259 (79) 1,079 (68) Couple characteristics,a n (%) or median (IQR) Married 1,540 (98) 1,552 (98) Years living with partner 7.1 (3.0 to 14.0) 7.1 (3.0 to 14.0) Number of children 2 (1 to 4) 2 (1 to 4) No children 368 (23) 342 (22) Years aware of discordant status 0.4 (0.1 to 2.0) 0.4 (0.1 to 2.0) Clinical characteristics, n (%) or median (IQR)

HIV‐1 plasma RNA, log10 copies/mL NA 3.9 (3.1 to 4.5) NA 3.9 (3.2 to 4.5) CD4+ cell count/mm3 NA 497 (380 to 664) NA 499 (375 to 663) Fully circumcised (men only) 540 (53) 177 (31) 509 (53) 202 (33) Using contraception (women only) 275 (49) 324 (32) 299 (48) 321 (33) Pregnant (women only) 0 135 (13) 0 118 (12) Curable STIb 93 (6) 122 (8) 126 (8) 137 (9) HSV‐2 seropositive 814 (54) NA 875 (58) NA

FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; HIV = human immunodeficiency virus; HSV = herpes simplex virus; IQR = interquartile range; NA = not applicable; RNA = ribonucleic acid; STI = sexually transmitted infection. a Couple characteristics were reported by the HIV‐1‐seronegative partner. b Neisseria gonorrhoeae, Chlamydia trachomatis, or Trichomonas vaginalis. Sources: Clinical Study Report6; Baeten et al., 2012.7

TABLE 8: SUMMARY OF BASELINE CHARACTERISTICS OF CDC TDF2 STUDY (HETEROSEXUAL MEN AND WOMEN) Characteristic CDC TDF2 FTC/TDF Placebo (n = 611) (n = 608) Age, n (%) 18 to 20 years 10 (1.6) 15 (2.5) 21 to 29 years 550 (90.0) 532 (87.5) 30 to 39 years 51 (8.3) 61 (10.0)

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

Characteristic CDC TDF2 FTC/TDF Placebo (n = 611) (n = 608) Male, n (%) 331 (54.2) 331 (54.4) Female, n (%) 280 (45.8) 277 (45.6) Education level, n (%) Primary or less 20 (3.3) 20 (3.3) Secondary 446 (73.0) 445 (73.2) Post‐secondary 145 (23.7) 143 (23.5) Marital status, n (%) Married 32 (5.2) 38 (6.2) Single 578 (94.6) 567 (93.3) Divorced or widowed 1 (0.2) 3 (0.5) Alcohol use in the past 3 months, n/n responses (%) 359/601 (59.7) 340/599 (56.8) Sexual behaviours at screening, n (%) Number of sexual partners in previous month 0 73 (11.9) 78 (12.8) 1 410 (67.1) 405 (66.6) 2 86 (14.1) 86 (14.1) ≥ 3 32 (5.2) 28 (4.6) Percentage of sexual episodes in which condoms were 81.4 (76.6 to 86.4) 79.2 (71.6 to 87.6) used with main or most recent sexual partner, % (range) Sex with known HIV‐positive partner in previous month Yes 21 (3.4) 22 (3.6) No 479 (78.4) 474 (78.0) STI diagnosed at screening, n/n tested (%) HSV‐2 seropositive 208/601 (34.6) 220/600 (36.7) Neisseria gonorrhoeae 12/578 (2.1) 12/565 (2.1) Chlamydia trachomatis 43/578 (7.4) 54/566 (9.5) Treponema pallidum 5/599 (0.8) 9/597 (1.5) Trichomonas vaginalis (women) 19/256 (7.4) 14/248 (5.6)

FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; HBV = hepatitis B virus; HIV = human immunodeficiency virus; HSV = herpes simplex virus; STI = sexually transmitted infection. Source: Thigpen et al., 2012.8

3.2.3 Interventions In all studies, patients were randomized 1:1 to FTC/TDF 200 mg/300 mg FDC or placebo, administered orally once daily. For the Partners PrEP study, a TDF 300 mg arm was also included (randomized 1:1:1); however, the results from this arm are not presented in this review. In addition to FTC/TDF, patients were given HIV infection prevention services at every scheduled visit, which included HIV testing, risk‐ reduction counselling, condoms, and diagnosis and treatment of symptomatic STIs (Table 9). In addition, adherence counselling was provided to all participants at each visit. Adherence counselling included reminding participants to contact study staff with questions about product use, as well as reminders to not share the study agent with other individuals.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

TABLE 9: ADDITIONAL INTERVENTIONS AT MONTHLY VISITS iPrEx Partners PrEP CDC TDF2  Dispense condoms  Provision of condoms and  Dispense condoms and  Risk‐reduction counselling contraceptives (if indicated) contraceptives (if indicated)  Adherence counselling  Couples HIV‐1 counselling  Risk‐reduction counselling  HIV‐1 pre‐ and post‐test  Risk‐reduction counselling  Adherence counselling counselling  Contraception counselling  HIV‐1 pre‐ and post‐test  Adherence counselling counselling  HIV‐1 pre‐ and post‐test counselling

HIV = human immunodeficiency virus. Sources: Grant et al., 2010,5 Baeten et al., 2012,7 Thigpen et al., 2012.8

Prohibited medications included antiretroviral therapies, interferon or interleukin therapies, aminoglycoside antibiotics, amphotericin B, cidofovir, systemic chemotherapeutic drugs, other drugs with significant nephrotoxic potential, and other drugs that may inhibit or compete for elimination via active renal tubular secretion.

In all included studies, adherence to study medication was monitored by participant self‐report and clinic‐based pill counts at pill dispensing visits.

3.2.4 Outcomes a) HIV‐1 Seroconversion In all included studies, the primary efficacy end point was the incidence of HIV‐1 infections based on pre‐specified testing algorithms. Paired HIV blood rapid tests were performed in parallel, and samples that elicited discordant results were retested. In the iPrEx study, discordant or positive results were retested or confirmed using Western blot, and if results were still unclear, a new specimen was taken from the participant. In the Partners PrEP study, discordant or positive results were retested or confirmed using two wells of an enzyme‐linked immunosorbent assay (ELISA) immunoassay. In the CDC TDF2 study, a single oral test was initially used, and participants with positive results were tested with paired blood HIV tests. All samples were confirmed with ELISA and ribonucleic acid polymerase chain reaction (RNA PCR), and inconclusive results would elicit a new sample collection and repeat testing with ELISA and PCR. In the iPrEx and Partners PrEP studies, paired HIV rapid tests that were concordant negative were accepted to be a negative result. In the CDC TDF2 study, negative initial oral test results were accepted to be a negative result.

In the iPrEx study, an HIV Events Committee was established to review all events and adjudicate any events that could not be confirmed through the testing algorithm. In the Partners PrEP study, an “Endpoint Committee” assessed the final determination of seroconversion. It is unclear whether there was a separate committee to adjudicate seroconversion events in the CDC TDF2 study. b) Sexual Behaviour In the iPrEx study, a structured interview for sexual behaviour was conducted at screening and every 12 weeks during follow‐up. The interview collected information about numbers of sexual partners, and numbers of receptive and insertive anal sexual partners with or without the use of condoms. In the Partners PrEP study, sexual behaviour information was collected at each monthly follow‐up visit. In the CDC TDF2 study, information on sexual episodes associated with condom use and number of sexual partners in the previous month was collected at each study visit.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA c) Sexually Transmitted Infections In the iPrEx study, evaluations for STIs were performed at least every 24 weeks. In the Partners PrEP study, STI screening was performed every 12 months. In the CDC TDF2 study, participants were tested annually for syphilis and every six months for gonorrhea, chlamydia, trichomoniasis, and vaginosis. In all studies, symptomatic STIs were to be diagnosed and treated at every monthly visit. d) Adherence to the Study Medication In all studies, adherence to the study medication was measured by survey and clinic pill count. e) Quality of Life Quality of life was not assessed in any of the included studies. f) HIV‐1 Resistance Participants who had HIV‐1 seroconversion detected were tested for plasma RNA levels, CD4+ cell counts, and viral drug resistance.

In the Partners PrEP study, the HIV‐1–positive partner was monitored for HIV‐1 disease progression at quarterly follow‐up visits, and was referred for ART if they met the national criteria for initiation due to CD4+ decline or clinical symptoms. g) Harms An adverse event (AE) was defined as any untoward medical occurrence in a clinical research participant who has been administered an investigational product and whose untoward medical occurrence does not necessarily have a causal relationship with the product. Clinical AEs were evaluated by a medical officer, and summaries of AE reports were reviewed with clinical medical staff and site investigators. A serious adverse event (SAE) was defined as any medical occurrence that resulted in death, that was considered life‐threatening, or that resulted in disability or hospitalization. Expedited AEs were defined to include all SAEs criteria with the addition of fetal loss, grade 2 creatinine elevation, and all bone fractures. All SAEs and expedited AEs were to be reported to the safety monitor within 48 hours.

3.2.5 Statistical Analysis a) Sample Size Calculation In the iPrEx study, a sample size of 3,000 participants (1,500 per group) was planned to produce the minimum target of 85 seroconversion events to yield a power of 80% with a one‐sided alpha of 0.05 to reject a null hypothesis of efficacy of 30% or less if the true efficacy were 60% or more. In the Partners PrEP study, a sample size of 3,900 HIV‐1–uninfected participants (1,300 participants per group) was planned to produce 191 seroconversion events to yield a power of 80% with a one‐sided alpha of 0.05 to reject a null hypothesis of 30% or less if the true efficacy were 60% or more, assuming a loss‐to‐follow‐ up rate of 18%. The planned sample size was increased after study initiation to 4,700 HIV‐1–uninfected participants, based on the incidence rate from another HIV‐1 prevention study (2.8 per 100 person‐ years) in serodiscordant couples.31 In the CDC TDF2 study, a sample size of 1,200 participants was planned to provide 80% power with a one‐sided alpha of 0.025 to detect a 65% reduction in HIV seroconversion, based on a background HIV incidence rate of 5%. b) HIV‐1 Seroconversion HIV‐1 infection as measured by seroconversion was assessed monthly, and was the primary end point for evaluating treatment effect. In the iPrEx and CDC TDF2 studies, the event time for HIV infection was the time of first site‐detected positive HIV‐1 RNA test with a dynamic range of at least 50 copies/mL. In 15

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA the Partners PrEP study, the event time for HIV infection was the time of the first site‐detected positive HIV‐1 antibody test.

In all studies, a Cox proportional hazards model stratified by study site using randomization group as a covariate was used for the primary analyses. In the iPrEx and Partners PrEP studies, two null hypotheses were tested: 1) zero efficacy with an alternative hypothesis of positive efficacy, using a one‐sided significance level for rejection of 0.025 for the comparison of FTC/TDF versus placebo; 2) less than 30% efficacy with a one‐sided Wald test versus an alternative hypothesis of more than 30% efficacy (corresponding with the premise for which the studies were powered). In the CDC TDF2 study, one null hypothesis was tested: less than 10% efficacy with an alternative hypothesis of more than 10% efficacy for the specific alternative of 65% efficacy (based on power calculation), using a one‐sided significance level for rejection of 0.025 for the comparison of FTC/TDF versus placebo. c) Sexual Behaviour In the CDC TDF2 study, logistic and Poisson regression models were used to assess differences over time in the proportion of sexual episodes associated with condom use in the previous month and the number of sexual partners in the previous month, respectively. d) Missing Data Participants who dropped out of the study, who were terminated, who refused further testing prior to the completion of follow‐up, or who died prior to completion of follow‐up were uninformatively censored at their last HIV‐1 test. vv vvvvvvvvvvv vvv vvvvvvv vvvv vvvv vvvvvvvvv vv vvv vvvvvvvv. e) Subgroup Analyses Subgroup analysis based on sex In the Partners PrEP and CDC TDF2 studies, subgroup analysis based on sex (female and male) was performed to investigate the uniformity of any treatment effects found in the overall analysis.

Subgroup analysis based on drug levels In the iPrEx study, a pre‐specified subgroup analysis was performed to investigate whether drug levels correlated with a protective effect. Participants with HIV infection were matched with two seronegative participants (one from each treatment group) according to study site, and the levels of emtricitabine and tenofovir were assessed in plasma and peripheral‐blood mononuclear cells.

In the Partners PrEP study, a post‐hoc analysis of drug level detection in plasma samples was performed by the manufacturer, using a case‐cohort design in which tenofovir levels in HIV‐1 seroconverters were tested in addition to 100 randomly selected HIV‐1–negative participants from each treatment group (200 total). Emtricitabine levels were not evaluated.

In the CDC TDF2 study, drug levels were assayed in HIV‐1 seroconverters using the samples collected most recently before the date of seroconversion. For each seroconverter, samples from three non‐ seroconverters were randomly chosen from the FTC/TDF group that had been collected closest to the corresponding seroconverter’s sample, and the samples were matched by sex and study site. f) Multiplicity No adjustments for multiple statistical testing were performed in the included studies.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA g) Analysis populations In the included studies, the following data sets were defined:

Modified Intention‐to‐Treat (mITT) Set vvv vvvvvvvvvv vvvvvvvvvvvv vvv vvvv vvvvvvvvv vvvvv vvvv and had at least one on‐study HIV assessment, excluding participants determined to be HIV‐positive at the time of randomization. This data set was used for primary efficacy analyses.

Safety Analysis Set In the iPrEx and Partners PrEP studies, this was defined as all randomized participants who were dispensed the study drug. In the CDC TDF2 study, this was defined as all randomized patients.

3.3 Patient Disposition In the iPrEx study, 10 participants (two FTC/TDF, eight placebo) were found retrospectively to have HIV‐ 1 infection at baseline, and approximately vvv of patients discontinued from the study. In the Partners PrEP study, nine participants (three FTC/TDF, six placebo) were found to have HIV‐1 infection at baseline, and 1% of participants discontinued from the study. Retention of partner participants in each study group was at least 96% over the course of the study (Table 11). In the Partners PrEP study, the most common reason for not dispensing study medication was pregnancy (Table 12). Time off study medication due to pregnancy and breastfeeding accounted for 5.3% of the follow‐up time among women (2.0% among all participants). In the CDC TDF2 study, 16 participants (nine FTC/TDF, seven placebo) did not receive any study drug, and three patients (one FTC/TDF, two placebo) were found to have HIV‐1 infection at baseline. In the CDC TDF2 study, more than 30% of participants discontinued from the study; the most common reasons for discontinuations were participant withdrawal, relocation, or loss to follow‐up. Overall, discontinuations were similar between treatment groups across the included studies.

TABLE 10: PATIENT DISPOSITION iPrEx Partners PrEP CDC TDF2 FTC/TDF Placebo FTC/TDF Placebo FTC/TDF Placebo Screened, N 4,905 7,856 2,533 Randomized, N (%) 2,499 4,758b 1,219 1,251 1,248 1,579 1,584 611 (100) 608 (100) (100) (100) (100)b (100)b Did not receive study drug, n (%) v v v v 9 (1) 7 (1) No follow‐up visit,a n (%) 25 (2) 23 (2) 8 (< 1) 10 (< 1) 0 0 HIV‐1–infected at baseline, n (%) 2 (< 1) 8 (< 1) 3 (< 1) 6 (< 1) 1 (< 1) 2 (< 1) Followed for seroconversion, n 1,224 (98) 1,217 (98) 1,568 (99) 1,568 (99) 601 (98) 599 (99) (%) Discontinuation, n (%) vvv vvvv vvv vvvv vv vvv vv vvv 208 (34) 189 (31) AE 25 (2) 28 (2) v vvvv v vvvv 0 0 Death 1 (< 1) 4 (< 1) 8 (1) 9 (1) 2 (< 1) 4 (< 1) Lost contact with participant vv vvv vv vvv v v 52 (9) 63 (11) Participant relocated vv vvv vv vvv v v 49 (8) 36 (6) Withdrawn by investigator v vvvv v vvvv v vvvv v vvvv 10 (2) 6 (1) Withdrawn by participant vv vvv vv vvv v vvvv v vvvv 90 (15) 74 (12)

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

iPrEx Partners PrEP CDC TDF2 FTC/TDF Placebo FTC/TDF Placebo FTC/TDF Placebo Other reason v vvvv v vvvv v v 5 (1) 6 (1) mITT, n (%) 1,224 (98) 1,217 (98) 1,568 (99) 1,568 (99) 601 (98) 599 (99) Safety, n (%) 1,251 1,248 1,579 1,584 611 (100) 608 (100) (100) (100) (100) (100)

AE = adverse event; FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; HIV‐1 = human immunodeficiency virus type 1; mITT = modified intention‐to‐treat. a Participants who did not have an on‐study follow‐up HIV test. b Four participants in the FTC/TDF group and 2 participants in the placebo group were determined not to meet eligibility criteria for the study after randomization. Sources: iPrEx Clinical Study Report (CSR),4 Grant et al., 2010,5 Partners PrEP CSR,6 Baeten et al., 2012,7 Thigpen et al., 2012,8 US Food and Drug Administration (FDA) Medical Review.28

TABLE 11: RETENTION OF PARTICIPANTS OVER TIME IN THE PARTNERS PREP STUDY Partners PrEP FTC/TDF Placebo Randomized, N (%) 1,579 (100) 1,584 (100) Retained, actual/expected (%) 6‐month visit 1,553/1,578 (98) 1,559/1,579 (99) 12‐month visit 1,379/1,414 (98) 1,378/1,406 (98) 18‐month visit 1,070/1,106 (97) 1,083/1,111 (97) 24‐month visit 753/784 (96) 760/783 (97) 30‐month visit 296/309 (96) 301/308 (98) 36‐month visit 16/16 (100) 18/18 (100)

FTC/TDF = emtricitabine/tenofovir disoproxil fumarate. Sources: Partners PrEP Clinical Study Report,6 Baeten et al., 2012.7

TABLE 12: PREGNANCIES IN THE PARTNERS PREP STUDY Partners PrEP FTC/TDF Placebo Total female HIV‐1–negative participants, n 566 621 Female participants reporting a pregnancy, n (%) 74 (13) 88 (14) Number of pregnancies reported 80 96 Incidence (95% CI) per 100 participant‐years 8.8 (vvvv vvvv) 10.0 (vvvv vvvv)

CI = confidence interval; HIV = human immunodeficiency virus; FTC/TDF = emtricitabine/tenofovir disoproxil fumarate. 6 7 Sources: Partners PrEP Clinical Study Report, Baeten et al., 2012.

3.4 Exposure to Study Treatments In the iPrEx study, participants were followed for 3,324 person‐years (median: 1.2 years; maximum: 2.8 years) at the time of the primary data cut‐off, with vvvv person‐years of follow‐up in the FTC/TDF group and vvvv person‐years of follow‐up in the placebo group. In the Partners PrEP study, HIV‐1–negative partner participants were followed for a total of 7,830 person‐years (median: 23 months; range: 1 to 36 months), including the TDF 300 mg group, at the time of the primary data cut‐off, with 2,616 person‐ years of follow‐up in the FTC/TDF group and 2,607 person‐years of follow‐up in the placebo group. In

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA the CDC TDF2 study, participants were followed for 1,563 person‐years (median: 1.1 years; maximum: 3.7 years) before the study was stopped.

The duration of exposure to the study drug was reported only for the iPrEx study. The mean (standard deviation) exposure was vvvv vvvvvv weeks in the FTC/TDF group and vvvv vvvvvv weeks in the placebo group. The median (range) exposure was vvvv vvvv vv vvvvvv weeks in the FTC/TDF group and vvvv vvvv vv vvvvvv weeks in the placebo group.

TABLE 13: DURATION OF EXPOSURE TO STUDY DRUG IN THE IPREX STUDY; SAFETY SET iPrEx FTC/TDF (n = 1,251) Placebo (n = 1,248) Overall exposure (weeks) Mean (SD) vvvv vvvvvv vvvv vvvvvv Median (range) vvvv vvvvv vvvvvv vvvv vvvvv vvvvvv

FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; SD = standard deviation. Sources: iPrEx Clinical Study Report,4 Grant et al., 2010.5

3.5 Critical Appraisal 3.5.1 Internal Validity Randomization was stratified by study site and for all studies, and in the CDC TDF2 study, randomization was also stratified by gender. Generally, baseline characteristics were balanced between FTC/TDF and placebo groups across studies.

There were discontinuations in approximately vvv of participants in the iPrEx study and in more than 30% of participants in the CDC TDF2 study. vvvvvvvvvvv vvv vvvvvvv vvvv vvvv vvv vvvvvvvvv and participants who discontinued early were censored at their last HIV‐1 test. Discontinuations were similar between the FTC/TDF and placebo groups in both studies, as well as the reasons for discontinuations. However, as a larger‐than‐expected proportion of participants was lost to follow‐up in the CDC TDF2 study, the study had not enrolled enough participants to meet the initial power calculations for the primary end point. Logistical challenges to recruitment precluded the expansion of the study, and the study was concluded early. Due to this limitation, results from the CDC TDF2 study need to be interpreted with caution.

No adjustments for multiple statistical testing were performed in the included studies. Therefore, results for secondary end points and secondary analyses to the primary end point need to be interpreted with caution due to the potential for type 1 error.

According to the clinical expert consulted by CDR, the HIV‐1 testing algorithms used in each study were quite rigorous and would likely screen out false‐positive results. Participants who had a positive test at a study visit had their samples from previous visits tested to determine the exact time point at which viral RNA was detectable.

3.5.2 External Validity The Partners PrEP and CDC TDF2 studies were conducted solely in African participants. According to the clinical expert consulted for this review, there may be differences in the standard of care and services available in countries outside of the Western context that may limit the generalizability of study results. In addition, premarital sex is less culturally acceptable in Botswana than in Western countries, which 19

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA may have limited the recruitment of these participants in the CDC TDF2 study, and potentially affect the reporting of sexual behaviours during the study.

In the iPrEx study, no Canadian participants were enrolled, and the majority of participants were from Hispanic countries. The clinical expert noted that the generalizability issues associated with a lack of Canadian participants would be related to the health care system and the availability of services for participants at risk of HIV infection in these countries compared with Canada.

According to the clinical expert, the MSM population enrolled in the iPrEx study was a very high‐risk population (average of 18 sexual partners in the past 12 weeks at baseline), which may be more extreme than what may be seen in Canadian clinical practice. In the Partners PrEP study, eligibility criteria were specified so that the HIV‐1–infected partner could not be eligible for ARTs at baseline, which may not be entirely generalizable to the Canadian population, where HIV‐1–infected individuals would be on ART with the goal of reducing viral load. However, not all HIV‐1–infected individuals in a relationship are initially aware of their status, and results from this study may be generalizable to that demographic.

In the Partners PrEP and CDC TDF2 studies, a requirement for enrolment was that the participant would not relocate for the duration of the study. This could potentially exclude several participants, particularly in a young, mobile population such as the one in the CDC TDF2 study. The logistics of conducting a study with relocating participants is challenging, although this would likely be a characteristic of the at‐risk population in Canada.

Patient groups reported that individuals at high‐risk of HIV‐1 experience anxiety and fear regarding the lack of control of their own sexual health, the possibility of HIV infection, and the stigma associated with a positive HIV status, and they have expectations that PrEP will be able to alleviate these concerns. However, quality of life outcomes were not assessed in any of the included studies, so the impact of FTC/TDF using PrEP on a patient’s well‐being is unknown.

Adherence according to pill counts and patient self‐report was generally high in all studies; however, adherence according to self‐report and pill count is subject to bias due to inaccurate reporting or potential disposal of pills prior to the study visit. Follow‐up visits in all three studies were conducted monthly, at which participants were tested for HIV‐1, provided with counselling, and treated for symptomatic STIs. According to the clinical expert, follow‐up visits would likely occur less frequently in clinical practice (i.e., likely every three months) compared with the monthly visits that occurred in the included studies. Therefore, interventions such as adherence counselling and risk‐reduction counselling would be provided less frequently in clinical practice, potentially limiting the generalizability of the studies.

3.6 Efficacy Only those efficacy outcomes identified in the review protocol are reported below (section 2.2, Table 2). See 0 for detailed efficacy data.

3.6.1 HIV‐1 Seroconversion In the iPrEx study, participants were followed for 1,659 person‐years in the FTC/TDF group and for 1,669 person‐years in the placebo group (median: 1.2 years; range: one day to 36 months) at the time of the primary data cut‐off (May 1, 2010). During this time, HIV‐1 seroconversion was observed in 110 participants, of which 10 had plasma HIV RNA subsequently detected from baseline specimens and were 20

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA excluded from the analyses (Table 14). Of the 100 participants with emergent HIV‐1 infection, 36 participants were in the FTC/TDF group (2.2 per 100 person‐years) and 64 participants were in the placebo group (3.8 per 100 person‐years), corresponding to a relative risk reduction of 44% (95% confidence interval [CI], 15% to 63%; P = 0.005). Follow‐up assessments of the primary end point included data through the end of DB treatment period (July 31, 2010 data cut‐off) and the end of treatment plus eight weeks of follow‐up (November 21, 2010 data cut‐off) (Table 19). The relative risk reduction in HIV‐1 seroconversion with FTC/TDF compared with placebo was similar to the primary analysis at the end of treatment (42%; 95% CI, 18% to 60%; P = 0.002) and at the end of treatment plus eight weeks of follow‐up (39%; 95% CI, 14% to 57%; P = 0.004). Although the primary end point at the various cut‐off dates were all statistically significant, the lower bound of the CIs was less than 30%, meaning the null hypothesis of efficacy of 30% or less could not be rejected. In the iPrEx study, for 100 participants on FTC/TDF for one year, a mean of 1.6 seroconversions (95% CI, 0.5 to 2.8) would be prevented compared with those on placebo.

In the Partners PrEP study, HIV‐1–negative partners were followed for 2,616 person‐years in the FTC/TDF group and for 2,607 person‐years in the placebo group at the time of the primary data cut‐off (median: 23 months; range: 1 to 36 months). During this time, HIV‐1 seroconversions were observed in 96 participants, of which 14 had plasma HIV RNA subsequently detected from baseline specimens and were excluded from the analyses (Table 14). Of the 82 participants with emergent HIV‐1 infection, 13 participants were in the FTC/TDF group (0.50 per 100 person‐years) and 52 participants were in the placebo group (1.99 per 100 person‐years), corresponding to a relative risk reduction of 75% (95% CI, 55% to 87%; P < 0.001). The lower bound of the CI exceeded 30%, ruling out the null hypothesis of efficacy of 30% or less. In the Partners PrEP study, for 100 participants on FTC/TDF for one year, a mean of 1.5 seroconversions (95% CI, 0.9 to 2.1) would be prevented compared with those on placebo.

In the CDC TDF2 study, participants were followed for 1,563 person‐years (median: 1.1 years; maximum: 3.7 years). During this time, HIV‐1 seroconversions were observed in 36 participants, of whom three had plasma HIV RNA subsequently detected from baseline specimens and were excluded from the analyses (Table 14). Of the 33 participants with emergent HIV‐1 infection, nine were in the FTC/TDF group (1.2 per 100 person‐years) and 24 were in the placebo group (3.1 per 100 person‐years), corresponding to a relative risk reduction of 62.2% (95% CI, 21.5% to 83.4%; P = 0.03).

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

TABLE 14: HIV‐1 SEROCONVERSION; MODIFIED INTENTION‐TO‐TREAT SET iPrEx Partners PrEP CDC TDF2 FTC/TDF Placebo FTC/TDF Placebo FTC/TDF Placebo (n = 1,224) (n = 1,217) (n = 1,576) (n = 1,578) (n = 601) (n = 599) HIV‐1 seroconversion Person‐years of follow‐up vvvv vvvv 2,616 2,607 1,563 Participants with 36 64 13 52 9 24 seroconversion events, n Rate per 100 person‐years vvv vvv 0.50 1.99 1.2 3.1 Hazard ratio (95% CI) 0.56 (0.37 to 0.85) 0.25 (0.13 to 0.45) NR Relative risk reduction, % 44 (15 to 63) 75 (55 to 87) 62.2 (21.5 to 83.4) (95% CI) P value 0.005 < 0.001 0.03 Absolute rate reduction, per vvv vvvvv vvvv vvv vvvvv vvvv NR 100 person‐years (95% CI)a

CI = confidence interval; FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; HIV = human immunodeficiency virus; mITT = modified intention‐to‐treat; NR = not reported. a Provided by the manufacturer.3 Source: iPrEx Clinical Study Report (CSR),4 Grant et al., 2010,5 Partners PrEP CSR,6 Baeten et al., 2012,7 Thigpen et al., 2012.8

In the iPrEx study, no HIV seroconversion event was reported during the DB treatment phase among any participant who initiated post‐exposure prophylaxis (PEP) (Table 15). The US Food and Drug Administration (FDA) conducted sensitivity analyses of the iPrEx data assuming that all FTC/TDF participants who received PEP and did not seroconvert would have become HIV‐infected on the day PEP began. The results of this analysis indicated that the use of PEP in the iPrEx study did not significantly affect the overall efficacy results.

TABLE 15: POST‐EXPOSURE PROPHYLAXIS IN THE IPREX STUDY; MODIFIED INTENTION‐TO‐TREAT SET iPrEx FTC/TDF Placebo (n = 1,224) (n = 1,217) Used PEP (Grant et al. values), n (%) 8 (< 1) 13 (1) Used PEP (FDA values), n (%) 13 (1) 20 (2)

FDA = US Food and Drug Administration; FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; PEP = post‐exposure prophylaxis. Sources: iPrEx Clinical Study Report,4 Grant et al., 2010,5 FDA.28

In the Partners PrEP study, approximately 30% of HIV‐1–positive partner participants initiated ART post‐ randomization during the study (Table 16). Because the risk of HIV transmission to the HIV‐1–negative partner participant is dependent on viral load, the FDA conducted sensitivity analyses to evaluate the effect of ART initiation on PrEP efficacy by censoring participants whose partner had initiated ART. The results of these analyses showed that the initiation of ART did not significantly affect the original conclusions.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

TABLE 16: ANTIRETROVIRAL THERAPY USE BY HIV‐1–INFECTED PARTICIPANTS IN THE PARTNERS PREP STUDY; SAFETY SET Partners PrEP FTC/TDF Placebo (n = 1,579) (n = 1,584) Number of participants reporting ART use during study follow‐up, n (%) vvv vvvv vvv vvvv Number of participants ever eligible for ART by national guidelines, n (%) vvv vvvv vvv vvvv ART = antiretroviral therapy; FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; HIV = human immunodeficiency virus. Source: Partners PrEP Clinical Study Report,6 Baeten et al., 2012.7 a) Subgroup analysis based on sex In the studies that looked at heterosexual male and female participants (Partners PrEP, CDC TDF2), subgroup analyses according to sex were performed on the primary efficacy end point (Table 20). In the Partners PrEP study, the relative risk reduction with FTC/TDF compared with placebo was 66% in females (95% CI, 29% to 84%) and 84% in males (95% CI, 54% to 94%). In the CDC TDF2 study, the relative risk reduction with FTC/TDF compared with placebo was 49% in females (95% CI, –22% to 81%) and 80% in males (95% CI, 25% to 97%). b) Analysis based on FTC/TDF drug levels In all studies, an analysis of drug level detection in HIV‐1 seroconversion cases and controls was performed. All studies examined the plasma levels of drug components, and the iPrEx study also looked at intracellular drug levels. In the iPrEx study, there was detectable plasma FTC and tenofovir (TFV) in 6% of HIV‐1 seroconversion participants compared with 48.6% of control participants. In the Partners PrEP study, there was detectable plasma TFV in 55.6% of HIV‐1 seroconversion participants compared with 83.1% of control participants. In the CDC TDF2 study, there was detectable plasma FTC and TFV in 50% of HIV‐1 seroconversion participants compared with approximately 80% of control participants.

TABLE 17: PLASMA EMTRICITABINE AND TENOFOVIR LEVELS BY HIV‐1 INFECTION STATUS iPrEx Partners PrEP CDC TDF2 Detectable drug Case (+) Control (–) Case (+) Control (–) Case (+) Control (–) Plasma FTC, n/n total (%) 2/33 (6.1) 17/35 (48.6) NR NR 2/4 56/69 (50.0) (81.2) Plasma TFV, n/n total (%) 2/33 (6.1) 17/35 (48.6) 20/36 374/464 2/4 55/69 (55.6) (80.6) (50.0) (79.7) Intracellular FTC, n/n total (%) 3/34 (8.8) 22/42 (52.4) ‐ ‐ ‐ ‐ Intracellular TFV, n/n total (%) 2/34 (5.9) 21/42 (50.0) ‐ ‐ ‐ ‐

‐ = not assessed; FTC = emtricitabine; HIV = human immunodeficiency virus; NR = not reported; TFV = tenofovir. Sources: iPrEx Clinical Study Report (CSR),4 Grant et al., 2010,5 Partners PrEP CSR,6 Baeten et al., 2012,7 Thigpen et al., 2012.8

3.6.2 Sexual Behaviour In the iPrEx study, the number of receptive anal intercourse (RAI) partners in the previous 12 weeks and the proportion of partners with whom anal intercourse was performed using condoms was analyzed throughout the course of the study (Table 21). The number of sexual partners with whom respondents had had RAI decreased after study enrolment from a mean of approximately 12 partners to a mean of less than five partners in the previous 12 months, and the percentage of those partners who used a

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA condom increased from 50% to more than 70%. The results of the assessments of sexual behaviours were similar between the FTC/TDF and placebo groups at all time points (P = 0.97).

In the Partners PrEP study, the proportion of HIV‐1–negative participants who reported having unprotected sex with their HIV‐1–positive partner in the prior month was assessed throughout the maximum 36‐month follow‐up period of the study (Table 22). At enrolment, 27% of HIV‐1–negative participants reported having had sex without a condom during the previous month. This percentage decreased during the follow‐up period to 13% and 9% at 12 and 24 months, respectively, and this was similar between treatment groups. The proportion of patients reporting engaging in sexual intercourse with outside partners did not differ across study groups (FTC/TDF, 29.9% versus placebo 29.1%).

In the CDC TDF2 study, the number of sexual partners in the previous month and the percentage of sexual episodes using condoms with the main or most recent casual sexual partner in the previous month were analyzed over 24 months after randomization. The percentage of sexual episodes using condoms with the main or most recent sexual partner was 81.4% (range: 76.6% to 86.4%) in the FTC/TDF group and 79.2% (range: 71.6% to 87.6%) in the placebo group at baseline, and remained similar between groups and was stable over 24 months (P = 0.87 for trend; P = 0.95 between treatment groups). The number of sexual partners in the previous month were similar between treatment groups throughout the study and declined slightly over time (P < 0.001 for trend; P = 0.95 between treatment groups).

3.6.3 Sexually Transmitted Infections In the iPrEx study, the incidence of STIs was analyzed by study visit as a separate outcome measure, with STI testing being performed every 24 weeks regardless of whether symptoms were reported (Table 23). There were no statistically significant between‐group differences in the incidence of syphilis, gonorrhea, chlamydia, genital warts, or genital ulcers during follow‐up.

In the Partners PrEP study, approximately 30% of participants reported having had sex with an outside partner (Table 24). The proportion of patients who reported any STI was similar between the FTC/TDF and placebo groups (4.8% versus 5.3%).

In the CDC TDF2 study, the incidence of STIs was reported as AE data (Table 25). The incidence of chlamydia and trichomoniasis (in women) were similar across treatment groups. There was a higher proportion of participants that reported having gonorrhea (4.6% versus 3.0% and sore genital ulcers (2.0% versus 1.0%) in the FTC/TDF group compared with the placebo group. A slightly higher proportion of patients reported having genital herpes in the placebo group compared with the FTC/TDF group (5.8% versus 4.6%).

3.6.4 Adherence In the iPrEx study, the mean and median rate of self‐reported pill use was similar between the FTC/TDF and placebo groups (mean: 88.7% versus vvvvvv median: 95.4% for both groups) (Table 26).

In the Partners PrEP study, study drug adherence was assessed using pill counts from returned study bottles (Table 27). As there was an FTC/TDF and a TDF arm and similar pills were not available for both, participants took two tablets daily. More than 98% of dispensed study bottles were returned, and 94% of dispensed study tablets were taken. Self‐reported adherence was also assessed at study visits. At vvv of total study visits where self‐reported adherence information was taken, participants indicated that

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA they had missed at least one dose of the study drug during the previous month, and at vv of study visits, participants reported having missed two or more consecutive doses.

In the CDC TDF2 study, rates of adherence were estimated to be similar across treatment groups according to pill counts (FTC/TDF, 84.1% versus placebo 83.7%) and self‐reported adherence for the preceding three days (FTC/TDF, 94.4% versus placebo 94.1%).

3.6.5 Quality of Life Quality of life was not assessed in any of the included studies.

3.6.6 HIV‐1 Drug Resistance In the iPrEx study, no FTC or TDF resistance mutations were detected among the 36 participants who had HIV‐1 seroconversion during the study. Among the 10 participants who were subsequently found to have had plasma HIV‐1 RNA at baseline (two FTC/TDF; eight placebo), two patients in the FTC/TDF group (M184V and M184I) and one patient in the placebo group (M184V, T215Y, and K103N) were found to have FTC‐resistant virus.

In the Partners PrEP study, resistance testing was performed in 63 of the 65 participants who had HIV‐1 seroconversion during the study in the FTC/TDF and placebo groups. One participant in the FTC/TDF group and one participant in the placebo group developed resistance mutations to non‐nucleoside reverse transcriptase inhibitors (NNRTIs) (K103N or V106A). Of the three patients in the FTC/TDF group who were subsequently found to have plasma HIV‐1 RNA at baseline, one participant developed FTC‐resistant virus (M184V).

In the CDC TDF2 study, one participant in the placebo group developed a K65R mutation intermittently at low levels after seroconversion. The one participant in the FTC/TDF group who had had HIV‐1 infection at baseline developed K65R, M184V, and A62V reverse transcriptase resistance mutations at high levels.

3.7 Harms Only those harms identified in the review protocol are reported below (see 2.2.1, Protocol). See 0 for detailed harms data.

3.7.1 Adverse Events Analyses of AEs by the iPrEx study team included all events reported through the May 1, 2010 cut‐off date, regardless of whether study drug had been discontinued. The manufacturer’s safety analyses included treatment‐emergent AEs occurring on or after the first study drug dispense date and on or before 30 days after the last study drug dose date and numbers are presented in Table 28. Overall, the incidence of AEs was similar across the FTC/TDF and placebo groups in the iPrEx study (69% versus 70%), the Partners PrEP study (86% versus 85%), and the CDC TDF2 study (91% versus 88%) (Table 18). Common AEs included upper respiratory tract infections, pharyngitis, diarrhea, and headache. In the CDC TDF2 study, common AEs also included abdominal pain, dizziness, nausea, vomiting, and weight loss.

3.7.2 Serious Adverse Events The incidence of SAEs was similar across the FTC/TDF and placebo groups in the iPrEx study (5% for both groups), the Partners PrEP study (7% for both groups), and the CDC TDF2 study (7% for both groups).

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

3.7.3 Withdrawals Due to Adverse Events In the iPrEx study, 2% of patients withdrew due to an adverse event in both treatment groups. In the iPrEx study, there was no pattern of AEs that led to discontinuation. In the Partners PrEP study, two participants in the FTC/TDF group and one participant in the placebo group withdrew due to an adverse event. In the Partners PrEP study, all discontinuations were due to an increase in blood creatinine level that was confirmed on repeat testing. In the CDC TDF2 study, no participants withdrew from the study due to an adverse event.

3.7.4 Mortality In the iPrEx study, one patient in the FTC/TDF group (motor vehicle accident) and four patients in the placebo group (one injury, one head injury, one gunshot wound, one unknown) died, with no deaths considered by the investigator to be related to study drug. In the Partners PrEP study, eight patients in the FTC/TDF group (one gunshot wound, one poisoning, one pulmonary tuberculosis, two road traffic accident, one gastroenteritis, one pulmonary embolism, one influenza‐like illness) and nine patients in the placebo group (three road traffic accidents, one hematemesis, one febrile infection, one electrocution, one suicide, one hypotension, one diabetic complication) died. Two of the deaths in the FTC/TDF group (pulmonary embolism, influenza‐like illness) were considered by the investigator to be possibly related to the study drug. In the CDC TDF2 study, two patients in the FTC/TDF group (one motor vehicle accident, one suicide) and four patients in the placebo group (two motor vehicle accident, one homicide, one cerebrovascular accident) died.

3.7.5 Notable Harms The incidence of elevated creatinine AEs was low across treatment groups in all included studies (2% or less).

The incidence of bone fractures was 1% or less across treatment groups in all included studies. Bone fractures were generally reported to be traumatic rather than pathological, resulting from motor vehicle accidents, direct force, or altercations.

TABLE 18: HARMS; SAFETY SET iPrEx Partners PrEP CDC TDF2 FTC/TDF Placebo FTC/TDF Placebo FTC/TDF Placebo (n = 1,251) (n = 1,248) (n = 1,579) (n = 1,584) (n = 611) (n = 608) AEs Participants with > 0 AEs, n 867 (69) 877 (70) 1,362 (86) 1,350 (85) 557 (91) 536 (88) (%) Common AEs Abdominal pain 24 (2) 15 (2) 3 (< 1) 2 (< 1) 155 (25) 156 (26) Depression 43 (3) 62 (5) 1 (< 1) 0 NR NR Diarrhea 46 (4) 56 (4) 38 (2) 39 (2) 76 (12) 65 (11) Dizziness NR NR 0 1 (< 1) 92 (15) 67 (11) Dysmenorrhea NA NA 2 (< 1) 2 (< 1) 32 (5) 34 (6) Headache 56 (4) 41 (3) 1 (< 1) 3 (< 1) 227 (37) 226 (37) Nausea 20 (2) 9 (< 1) 1 (< 1) 0 113 (19) 43 (7) Pelvic inflammatory disease NA NA 48 (3) 55 (3) 6 (1) 10 (2) Pharyngitis 70 (6) 85 (7) 18 (1) 15 (1) 39 (6) 37 (6)

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

iPrEx Partners PrEP CDC TDF2 FTC/TDF Placebo FTC/TDF Placebo FTC/TDF Placebo (n = 1,251) (n = 1,248) (n = 1,579) (n = 1,584) (n = 611) (n = 608) Rash NR NR 3 (< 1) 2 (< 1) 39 (6) 42 (7) Urethritis 49 (4) 63 (5) 16 (1) 20 (1) NR NR URTI 42 (3) 47 (4) 159 (10) 142 (9) 231 (38) 241 (40) Vomiting NR NR 4 (< 1) 0 69 (11) 43 (7) Weight loss 27 (2) 14 (1) 4 (< 1) 6 (< 1) 75 (12) 61 (10) SAEs Participants with > 0 SAEs, n 60 (5) 67 (5) 115 (7) 118 (7) 115 (7) 118 (7) (%) WDAEs Participants with > 0 WDAEs, 25 (2) 27 (2) 2 (< 1) 1 (< 1) 0 0 n (%) Deaths Number of deaths, n (%) 1 (< 1) 4 (< 1) 8 (< 1) 9 (< 1) 2 (< 1) 4 (< 1) Notable harms, n (%) Renal AEs Elevated creatininea 25 (2) 14 (1) 20 (1) 13 (1) 1 (< 1) 0 Bone AEs Bone fracture 15 (1) 11 (1) 9 (< 1) 13 (1) 7 (1) 6 (1)

AE = adverse event; FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; SAE = serious adverse event; WDAE = withdrawal due to adverse event; URTI = upper respiratory tract infection. a Defined as an increase in serum creatinine of at least 1.5 times the baseline value. Sources: iPrEx Clinical Study Report (CSR),4 Grant et al., 2010,5 Partners PrEP CSR,6 Baeten et al., 2012,7 Thigpen et al., 2012.8

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

4. DISCUSSION

4.1 Summary of Available Evidence Three DB, placebo‐controlled RCTs assessing the safety and efficacy of once‐daily FTC/TDF200 mg/300 mg as PrEP in combination with HIV prevention services for individuals at high risk of acquiring HIV‐1 infection met the inclusion criteria for this review. The iPrEx study (N = 2,499) was an international study conducted in adult MSM that continued until at least 85 seroconversion events occurred. Participants who completed the iPrEx study had the option of enrolling in a 72‐week open‐label extension (OLE) study along with participants who had completed other MSM studies (see APPENDIX 5). The Partners PrEP study (N = 4,758) was conducted in adult Kenyan and Ugandan sexually active, serodiscordant, heterosexual couples, and followed participants for 24 to 36 months. The CDC TDF2 study (N = 1,219) was conducted in Botswanan heterosexual men and women between 18 and 39 years who were sexually active where participants were planned to be treated for four years. The CDC TDF2 study was concluded early due to the lower‐than‐expected rate of retention of participants. In all studies, study visits were scheduled every four weeks and included drug dispensing, rapid testing for HIV‐1 antibodies, adherence counselling, risk‐reduction counselling, condom promotion, and treatment of symptomatic STIs. In all studies, the primary end point was the incidence of HIV‐1 infections based on rapid testing at each monthly visit using pre‐specified testing algorithms. Other end points evaluated included sexual behaviour, the incidence of STIs, adherence to study drug, and HIV‐1 drug resistance in seroconversion participants.

The main limitations of the included studies were the generalizability of results due to the enrolled population. The iPrEx study enrolled MSM that were at very high risk of acquiring HIV‐1, the Partners PrEP study included serodiscordant couples in which the HIV‐1–positive partner was not to be taking ART, and the majority of enrolled participants were from Hispanic (iPrEx) or African (Partners PrEP and CDC TDF2) countries. Measures of treatment adherence were based on pill count and patient self‐ report, and may therefore have been subject to bias. As no adjustments for multiple testing were performed for secondary end points, the results need to be interpreted with caution. Although quality of life was cited as an important outcome according to patient‐group input, health‐related quality of life was not measured in any of the studies.

An ongoing phase 4, two‐year, randomized, open‐label study (planned N = 5,000) conducted in the UK compared FTC/TDF PrEP administered immediately to FTC/TDF PrEP delayed for one year in adult MSM (see APPENDIX 6). A phase 3, DB RCT (N = 414) conducted in France and Canada assessed the safety and efficacy of TDF/FTC administered as on‐demand PrEP in adult MSM (see APPENDIX 7.)

4.2 Interpretation of Results 4.2.1 Efficacy The three studies included in this review were conducted in different populations, but inclusion and exclusion criteria for each study allowed for the enrolment of individuals at risk for acquiring HIV‐1 infection who would likely be able to tolerate once‐daily FTC/TDF FDC 200 mg/300 mg for PrEP. However, the iPrEx study and Partners PrEP studies excluded patients with active alcohol or drug use considered sufficient to hinder compliance, which may reduce the generalizability of results to the at‐ risk population in Canada. In addition, none of the studies were conducted in Canada, with the iPrEx study enrolling mainly Hispanic participants from South American countries, and the Partners PrEP and CDC TDF2 studies enrolling African participants from Kenya, Uganda, or Botswana. The clinical expert consulted by CDR noted that differences in metabolism or biological effects of FTC/TDF between races

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA are not known, but there may be differences in the health care systems and access to HIV prevention services in developing countries that may limit generalizability of the included studies to the Canadian context. In the iPrEx study, the adult MSM participants enrolled had characteristics that would be defined as a very high‐risk population, with participants having had a mean of 18 partners in the previous 12 weeks at baseline. According to the clinical expert, this MSM population may be at higher risk than patients who would normally be seen in a Canadian clinic. In the Partners PrEP study, HIV‐1– infected partner participants were not to be eligible for ART according to national guidelines, which limits the generalizability of results to serodiscordant couples in which the HIV‐1–infected partner is currently being treated with ART. However, the goal of ART in HIV‐1–infected patients is suppression of viral replication as indicated by a plasma HIV‐1 viral load below 40 copies/mL, at which level the risk of transmission would be low and the efficacy of FTC/TDF as PrEP would be difficult to demonstrate.32 The CDC TDF2 study enrolled a young heterosexual population between 18 and 39 years of age, which is relevant to the at‐risk population in Canada. However, due to the mobile nature of this young population in Botswana, retention of participants in the CDC TDF2 study was difficult and the study was concluded early due to the logistical challenge of increasing recruitment to meet revised power calculations.

The incidence of HIV‐1 seroconversion was the primary efficacy end point in all studies. Paired rapid HIV tests were administered at each monthly visit, and discordant or positive results were retested or confirmed using rigorous testing algorithms. In all studies, there was a statistically significantly reduced risk of HIV‐1 seroconversion for patients receiving FTC/TDF compared with placebo. The relative risk reductions with FTC/TDF versus placebo ranged from 44% (95% CI, 15 to 63) in the iPrEx study to 75% (95% CI, 55 to 87) in the Partners PrEP study. The FDA evaluated the robustness of the results from the iPrEx and Partners PrEP studies by conducting sensitivity analyses of participants who initiated PEP therapy and HIV‐1–positive partner participants who initiated ART, which did not significantly alter the primary analysis. The reason for the differences in relative risk reduction of HIV‐1 seroconversion with FTC/TDF versus placebo across studies is unclear, but may be explained in part by adherence to therapy. Results from the analyses of plasma drug levels among HIV‐1 seroconverters and non‐seroconverters in the included studies suggest that a lower proportion of HIV‐1 seroconverters had detectable drug levels than non‐seroconverters. Subgroup analyses based on sex in the Partners PrEP and CDC TDF2 studies did not suggest a difference in the efficacy of FTC/TDF based on sex. However, a pharmacokinetic study (N = 15) demonstrated that a single dose of FTC/TDF results in tenofovir concentrations that were 100‐fold higher in rectal tissue than in vaginal and cervical tissues, and detectable for 14 days after administration.33

Adherence based on pill counts and self‐report was high across studies (> 80%), and adherence counselling was given at each monthly visit. Due to the subjective nature of these measures, there is the potential for misreporting by participants. In the Partners PrEP study, an adherence sub‐study (N = 1,147) was conducted in which unannounced, home‐based pill counts were conducted monthly for the first six months and then quarterly.34 Results from this sub‐study suggested that adherence was high in the Partners PrEP study and corroborated with the results from self‐report and pill counts in the full study.34 High adherence seen in the Partners PrEP study may also have been due to the enrolled population, in which the HIV‐1–negative partner in a serodiscordant, monogamous relationship may receive support from their HIV‐1–infected partner and be motivated to preserve the relationship.34 No adherence sub‐studies were conducted in iPrEx and CDC TDF2. Two DB, placebo‐controlled RCTs (VOICE, phase 2b, N = 5,029; FEM‐PrEP, phase 3, N = 2,120) evaluating the safety and efficacy of FTC/TDF for PrEP were conducted in sexually active African women at risk of acquiring HIV infection.35,36 Both studies were terminated early due to a lack of efficacy, which was found to be due to poor adherence. In the 29

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

FEM‐PrEP study, analysis of plasma and intracellular drug levels among a sub‐cohort of the population demonstrated that 12% had achieved good adherence, 23% had rarely taken FTC/TDF, and 60% had had fluctuating adherence, despite self‐reporting of high adherence during the trial.37 Participants had difficulty accurately reporting their adherence in a clinical trial setting because they assumed that reporting poor adherence would result in negative consequences.37

On‐demand PrEP is not a Health Canada–approved regimen for FTC/TDF 200 mg/300 mg; however, one study has been conducted to assess on‐demand PrEP therapy with FTC/TDF due to the difficulty of adhering to a daily regimen.38 The IPERGAY study was a DB, placebo‐controlled RCT (N = 414) conducted in adult MSM in France and Canada to assess the safety and efficacy of on‐demand PrEP with FTC/TDF (see APPENDIX 7).38 In the IPERGAY study, participants were to take two pills 2 to 24 hours before sex, followed by a third pill 24 hours after the first drug intake and a fourth pill 24 hours later. For consecutive episodes of sexual intercourse, participants were to take one pill per day and two post‐ exposure pills after the last episode. Results from the IPERGAY study suggest that there is a reduction in the incidence of HIV‐1 seroconversions in MSM with on‐demand FTC/TDF compared with placebo (431.3 person‐years follow‐up; relative risk reduction 86%; 95% CI, 40 to 98), although results need to be interpreted with caution as the study was concluded early after stopping rules were met and continued as an open‐label RCT. Adherence was suboptimal, with 43% of participants taking the drug correctly, 29% taking it at a suboptimal dose, and 28% of participants not taking any drug. A four‐month, DB, placebo‐controlled RCT (N = 72) was conducted in healthy African MSM and female sex workers to assess adherence to daily versus intermittent PrEP regimens; results from this small study suggested that adherence rates were better with daily dosing than with intermittent, coitally timed dosing.39 As this was a small study, results need to be interpreted with caution.

In addition to daily FTC/TDF or placebo, participants were provided with risk reduction counselling at each monthly visit and connected to local prevention services when required in the studies. Overall, sexual behaviour was similar between the FTC/TDF and placebo groups across studies. In the iPrEx study, the number of RAI partners in the previous 12 weeks decreased during the study, and the percentage of partners who used a condom increased in both FTC/TDF and placebo groups. In the Partners PrEP study, the proportion of participants reporting having had sex without a condom in the previous month decreased during the study in both FTC/TDF and placebo groups. In the CDC TDF2 study, the percentage of sexual episodes using condoms with the most recent sexual partner remained constant during the study, and the number of sexual partners in the previous month declined slightly over time. Because sexual risk behaviour was self‐reported, results may be biased by social desirability; the incidence of STIs may be a more objective measure of sexual behaviour. However, the proportion of participants with STIs over time was not reported in any of the included studies, although the incidence of STIs was similar between the FTC/TDF and placebo groups.

In the patient‐group submission, participants expressed that FTC/TDF PrEP would alleviate their anxiety and fear of becoming HIV‐positive after engaging in risky sexual behaviour, whether it be condomless sex or sex with HIV‐1–positive partners (see APPENDIX 1). This highlights the potential issue of sexual risk compensation, or engaging in more risky sexual behaviours if receiving PrEP with FTC/TDF. Risky sexual behaviours decreased or stayed constant over time in both the FTC/TDF and placebo groups across studies. The interpretation of this result, however, is limited because of the DB nature of the studies’ participants. A secondary analysis of the iPrEx study found that there was no evidence of sexual risk compensation in participants who believed they were receiving FTC/TDF.24 The PROUD study is an ongoing, real‐world, open‐label RCT study evaluating the safety and efficacy of FTC/TDF as PrEP for MSM in the UK administered immediately compared with delaying PrEP for a year (see APPENDIX 6).40 30

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

A sample size of 5,000 has been planned, and results from the first 544 participants suggested that there were no statistically significant differences in bacterial STIs between the group that received immediate treatment and the delayed treatment group. When compared with the iPrEx study, PROUD demonstrated a larger relative risk reduction in HIV‐1 seroconversion with FTC/TDF compared with no therapy (relative risk reduction 86%; 95% CI, 64 to 96). However, the population in the PROUD study was highly selective and was at substantially higher risk of acquiring HIV infection than the overall MSM population attending sexual health clinics in England (9.0 HIV‐1 seroconversions per 100 patient‐years in the delayed group; median 10 partners in past 90 days).41

4.2.2 Harms Overall, the incidence of AEs was similar between the FTC/TDF and placebo groups across the included studies. Common AEs included pharyngitis, upper respiratory tract infection, diarrhea, and headache. The incidence of certain AEs was higher in the CDC TDF2 study, and also included abdominal pain, dizziness, nausea, vomiting, and weight loss. In the 72‐week OLE study that included participants who completed MSM studies including iPrEx (N = 1,603; 95% from iPrEx study), the most common AEs that resulted in stopping FTC/TDF use were nausea and abdominal pain (see APPENDIX 5).

The safety profile of FTC/TDF has been well studied in HIV‐1–infected patients and is comparable to that of TDF alone.42 Notable harms associated with FTC/TDF include renal AEs and bone AEs. In the included studies, the incidence of elevated creatinine AEs did not exceed 2% in any group across studies, and the incidence of bone fractures did not exceed 1% across studies, with the majority of bone fractures being trauma‐related. In the iPrEx and Partners PrEP studies, renal function was further analyzed by measuring creatinine clearance and estimated glomerular filtration rate (eGFR) over time. In both studies, FTC/TDF was associated with a decrease in creatinine clearance and decline in eGFR over time compared with placebo.25,29,43 However, both creatinine clearance and eGFR decreases were reversible after discontinuation of treatment.25,29,43 The Health Canada product monograph recommends that FTC/TDF for PrEP not be used in HIV‐1–uninfected individuals with creatinine clearance below 60 mL/min, which is consistent with the characteristics of the participants enrolled in the iPrEx and Partners PrEP studies.22

In the iPrEx and CDC TDF2 studies, bone mineral density (BMD) sub‐studies were conducted to evaluate the effect of FTC/TDF on bone loss.44,45 In both the iPrEx BMD sub‐study (N = 498) and the CDC TDF2 BMD sub‐study (N = 220), small but statistically significant decreases in spine and hip BMD were observed with FTC/TDF compared with placebo.44,45 The Health Canada product monograph recommends that an assessment of BMD should be considered in patients who have a history of pathologic bone fracture or who are at risk for osteopenia or osteoporosis.22 Participants with these characteristics were not enrolled in the iPrEx, Partners PrEP, and CDC TDF2 studies, which limits the generalizability of these safety results to that population.

The Health Canada product monograph recommends that FTC/TDF for PrEP be used as part of a comprehensive prevention strategy that includes safer sex practices, knowledge of their HIV‐1 status and that of their partner(s), and regular testing for STIs.22 In the included studies, follow‐up visits were conducted monthly and included HIV testing, risk reduction counselling, adherence counselling, treatment of symptomatic STIs, and provision of condoms and contraceptives. According to the clinical expert, participants on PrEP therapy would not likely be seen as frequently in clinical practice, and follow‐up visits would likely be conducted every three months. According to the Health Canada product monograph, the use of FTC/TDF 200 mg/300 mg for PrEP must be prescribed only to individuals confirmed to be HIV‐negative immediately prior to initial use and periodically (at least every three months) during use.22 31

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

4.3 Potential Place in Therapy The information in this section is based on information provided in draft form by the clinical expert consulted by CDR reviewers for the purpose of this review.

Sexual health services are available in most communities, and provide counselling, condoms, testing for HIV and other STIs, and treatment for STIs. In spite of the fact that the sexual transmission of HIV is significantly reduced by the use of condoms, significant numbers of new HIV infections occur annually.12,13 Aside from barrier methods, other interventions to reduce the sexual transmission of HIV include male circumcision and through treatment of STIs.46‐49 PEP with antivirals after sexual exposure to HIV has not been studied in RCTs, but other evidence (animal transmission models,50 perinatal clinical trials,51 observational studies of health care workers receiving prophylaxis after occupational exposures,52 and observational and case studies of PEP use after sexual exposure)53‐55 suggests its effectiveness. However, antivirals are not approved for this indication, and access may be limited by cost and timely access to providers.

There remains, therefore, the need for further interventions to help prevent HIV transmission, according to the clinical expert consulted for this review. The clinical trials for PrEP with Truvada demonstrate that Truvada reduces the risk of HIV acquisition and is well tolerated. Long‐term kidney and bone toxicities are possible, but according to the clinical expert consulted, are uncommon and manageable. There are no data available as to the effectiveness of other antivirals to reduce HIV acquisition when used as PrEP, aside from tenofovir, which appears to be less effective than Truvada.7

PrEP, in conjunction with safe practices, would be considered for HIV‐negative adults identified as being at high risk for HIV infection through sexual exposure. The clinical expert indicated that these patients would likely come to the attention of health care providers through self‐referral, through referral from primary care physicians after the diagnosis of an STI or identification of an ongoing significant sexual risk, or after the provision of PEP after a potential sexual exposure to HIV. Although PrEP could be a prevention option for any heterosexual or homosexual person considered at high risk for HIV infection, experience from a US cohort of persons using PrEP found that 95.1% of users identified as homosexual men.56 In Canada, there are an estimated 369,500 MSM, of whom an estimated 329,870 are not HIV‐ infected.57

Aside from reduced kidney function, there would be few barriers to the prescription of Truvada for PrEP. HIV seronegative status would be required for the initiation of treatment, and PrEP would likely be provided by specialist and family physicians by quarterly prescription, with ongoing counselling and testing for HIV and other STIs. The duration of treatment would be indefinite, presumably determined by the ongoing risk for HIV infection.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

5. CONCLUSIONS

Three DB, placebo‐controlled RCTs assessing the safety and efficacy of once‐daily FTC/TDF 200 mg/300 mg as PrEP in combination with HIV prevention services for individuals at high risk of acquiring HIV‐1 infection were included in this review. The iPrEx study was conducted in adult MSM, the Partners PrEP study was conducted in adult Kenyan and Ugandan sexually active, serodiscordant heterosexual couples, and the CDC TDF2 study was conducted in young Botswanan heterosexual men and women. Results from all studies suggest that there was a statistically significant reduction in the incidence of HIV‐1 seroconversion with FTC/TDF compared with placebo. Treatment adherence based on pill count and self‐report was high across studies, but may be subject to bias. Sexual behaviour and the incidence of STIs did not differ between FTC/TDF and placebo groups, and small improvements were seen over time, although the reliance on participant interviews may also have been vulnerable to bias. Although quality of life was cited as an important outcome according to patient‐group input, this was not evaluated in the included studies. Overall, the incidence of AEs was similar between FTC/TDF and placebo groups, and the incidence of renal and bone AEs was low across studies. None of the studies were conducted in Canada, and there may be generalizability issues, as the included studies were conducted mainly in Hispanic and African countries where health care services may not be as accessible as in the Canadian setting.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

APPENDIX 1: PATIENT INPUT SUMMARY

This section was prepared by CADTH staff based on the input provided by patient groups.

1. Brief Description of Patient Group(s) Supplying Input Three patient groups provided input for this submission.

Toronto Sex Workers Action Project (Maggie’s) is an organization run for and by local sex workers. Their mission is to assist sex workers to live and work in safety and dignity by fighting to control their own bodies, sexuality, and working lives. Maggie’s has collaborated with the Sistering and Women’s HIV/AIDS Initiative in order to collect data about the experiences of cis (born female and self‐identified as female) and trans (born male and self‐identified as female) women living in poverty and who face a high risk of human immunodeficiency virus (HIV) infection or who are HIV‐positive. Maggie’s declares no conflicts of interest in the preparation of this submission.

The Canadian Treatment Action Council (CTAC) is Canada’s national non‐governmental organization addressing access to treatment, care, and support for people living with HIV and hepatitis C. CTAC meaningfully engages community members, service providers, policy‐makers, and other stakeholders to identify, develop, and implement policy and program solutions. In fiscal year 2015–2016, CTAC received unrestricted organizational and educational grants from Gilead Sciences, AbbVie, and ViiV Healthcare Canada. No other company or organization played a role in preparing CTAC’s submission.

The AIDS Committee of Toronto (ACT) was founded to address the emerging and urgent challenges of HIV and acquired immune deficiency syndrome (AIDS), and has since grown into the largest HIV service organization. ACT offers a comprehensive slate of free and confidential capacity‐building programs and support services for people living with HIV. They also work as community advocates and sexual health educators to reduce the rates of HIV transmission and prevent new infections from occurring. ACT is funded in part by Gilead Sciences Canada, along with several other pharmaceutical companies. Gilead’s contributions are restricted to funding the Community Health Forums, and are not used for any other purpose. ACT declares no conflicts of interest in the preparation of this submission

2. Condition‐Related Information Maggie’s gathered information through focus groups and one‐on‐one interviews recruited through open calls for participation and outreach to community partners. In total, 26 cis or trans women at high‐risk of HIV infection or who were HIV‐positive were used to inform this submission.

CTAC gathered information through anonymous online surveys following two public national consultation Webinars advertised on CTAC’s website, social media and member or partner communications. In total, 20 completed surveys were used to inform this submission. Fifteen were male, two were female, and one was a transgender male. Seventeen participants reported gay, bisexual, or queer sexual orientation.

ACT gathered information through focus groups and one‐on‐one interviews recruited through ACT’s existing social media, email lists from program staff, and recruitment posters advertised through community partners. A total of 23 gay, bisexual, or queer men at high‐risk of HIV infection or who are HIV‐positive participated and were used to inform this submission.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

According to CTAC, gay, and other men who have sex with men (MSM) have been disproportionately affected by the HIV epidemic in Canada since the 1980s, representing the majority of existing and new infections. CTAC submits that these men’s experiences of physical, mental, and sexual health, and their intention and efforts to remain HIV‐negative, must be appreciated in this context. HIV‐negative individuals reported experiences of being in a situation in which they felt unable, or were unable, to control their sexual health, had a significant fear of HIV infection, and were experiencing the stigma associated with a positive HIV status. They described recurring anxiety associated with a range of sexual encounters with others whose HIV status is positive or uncertain. The people who provided input reported that the fear and anxiety associated with HIV status has a significant negative effect on sexual and mental health, as well as on personal and sexual relationships. “Before PrEP I was living in fear of ‘when’ I would become HIV+.” Some reported that the anxiety of becoming HIV‐positive is so debilitating that it affects their professional life. “I didn’t know what to do the first time the condom broke, in 2013. I was doing my Master’s [at a university.] After I was going through a terrible time at university because I was thinking about it all of the time. For me it was very difficult to work on my thesis.” Others reported that the anxiety is so great that they are unable to have any sort of relationship with those who are HIV‐positive or with those whose HIV status is uncertain. “Every time I get tested, and I get tested every three months, the week before I’m shaking and worried I’m going to test positive — I’m really, really anxious about it.” “It’s hard to get intimately involved with someone when you’re worried about them being HIV‐positive and having not told you...”

Caregivers were defined as either HIV‐positive individuals in a relationship with HIV‐negative individuals or counsellors or service providers working with HIV‐negative individuals. HIV‐positive caregivers reported anxiety and struggles over being responsible for managing the risk of HIV transmission and the barriers arising from using condoms during intercourse. They also reported their fear of HIV transmission as being a burden in forging meaningful relationships with HIV‐negative partners.

One patient group (Maggie’s) emphasized women’s concerns associated with HIV transmission, particularly when the risk of violence is present: “... having access to PrEP would mean I don’t have to worry about not being able to protect myself if I’m a victim of sexual assault or if a condom breaks or if someone takes the condom off while having sex. This is a huge risk. And it is something my partner threatens me about.”

3. Current Therapy‐Related Information Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) is the first therapy approved for HIV pre‐ exposure prophylaxis (PrEP). In the absence of a therapeutic drug for HIV prevention, all patient groups reported that currently the most common method to prevent HIV infection is the use of condoms. However, most participants emphasized that condoms alone are not enough to quell their fear and anxiety of becoming infected with HIV. They expressed their distress with the lack of efficacy of condoms, actual and anticipated condom breakage, and the potential that penetrative sexual partners will remove condoms during intercourse. Some reported their dislike or hatred of condoms, for a variety of reasons. For some, condoms are a barrier to intimacy or trust between sexual and intimate partners, which negatively affects these relationships. “I found myself engaging in condomless sex with casual partners, especially when drinking. This led to stress and anxiety about HIV. It also caused upset in my relationship with my partner, as it disrupted our sex life when we needed to use condoms with each other as a result of me engaging in high‐risk sex with other people. I experienced guilt and shame around my sexual choices, because I did not want to put my partner at risk.” Others reported a lack of pleasure or erectile problems when using condoms as a preventive measure. For these reasons, some participants noted that they are not using condoms during intercourse by choice, which they report is a 35

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA cause for shame as they are knowingly putting themselves at risk. “I often don’t like using condoms... and there’s a lot of guilt and shame that comes with wanting that, as well. To know that in a situation I can be spontaneous and not worry about the stress or the post‐coital shame — whatever comes after it — that just knowing that I can take preparation before I actually get put in that situation where you don’t think clearly or rationally, that I can prepare myself to have a backup plan in that case... To have that safety net that if something does go wrong...” Others reported an increasing prevalence of pressure to engage in, and expectation of, condomless anal intercourse in the sexual networks of gay and other MSM. HIV‐positive caregivers highlighted that they often bear the responsibility of education associated with HIV, infection risk, and risk management strategies. They also expressed the struggle to balance the responsibility of HIV management and barriers to intimacy (i.e., condoms).

Sex workers were reported to be pressured into condomless intercourse due to financial incentives. “There is more risk in the sex industry and the choice of not using protection because it is more money, you know, because people want to go bareback and they pay more money because you are taking that risk on.” (Note: Almost all participants in this focus group agreed with this).

4. Expectations About the Drug Being Reviewed Generally, positive experiences and expectations were reported by patients both with and without experience with FTC/TDF. Patient groups highlighted, based on patient reports, that the stress, anxiety, and fear associated with becoming HIV‐positive would lessen, and that the barriers to intimacy or relationships between HIV discordant individuals would diminish with the use of FTC/TDF. Those who had experience with the drug reported a better sex life, greater ease with sexuality and sexual expression, and improved relationships with their sexual or intimate partners. “The feeling of protection that I get from PrEP has allowed me to enjoy sex more and more frequently, explore condomless sex safely with my primary partner, and eliminated my anxiety over illness as I no longer feel at significant risk of seroconversion. PrEP has changed my life.” Some patients reported that the stigma associated with HIV‐positive individuals has been completely eliminated with the use of FTC/TDF, opening the door to relationships otherwise unexplored. “I’m looking to have a relationship and I’ve met a lot of great poz guys, but I could never go further with them. But if I was on PrEP I could go further.” “Since being on PrEP, my anxiety over sex has largely been eliminated and I personally have learned that the stigma toward HIV+ people can be eradicated— it has for me!”

Some patients reported that the use of FTC/TDF is an added layer of protection along with safe sex practices (i.e., condoms). Other patients highlighted that they are looking for alternative options for safe sex practices that allow for more intimate relations. “PrEP allows me to connect and be intimate with my sexual partner in a way that was not possible with condoms...”

Some indicated that adherence to FTC/TDF is much easier and practical than using condoms. “... it is much easier to be consistent about my PrEP use. I just take it with my vitamin every morning. I don't need to negotiate condom use in the heat of the moment. PrEP is much better in this way. Even if I missed a dose at some point, I'd still have very high levels of protection. But if I don't use a condom, I have zero risk reduction for that time.” Some patient suggested that they would rather temporarily take FTC/TDF instead of taking a lifetime of HIV treatment: “I’d rather be on PrEP when I’m young because the alternative is me getting HIV and having to take those drugs anyway, and that’s for my entire life. I could be on them for 30 or 40 years because I got HIV or I could be on them for 10 years, prevent it, and then go back off of them.” Maggie’s particularly highlights that with the use FTC/TDF there would be a reduced risk of violence when negotiating HIV prevention before intercourse.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

Patients also reported their willingness to accept certain adverse events (AEs) associated with FTC/TDF, as they are eclipsed by the benefits of using this drug as an HIV prevention method. AEs such as nausea, vomiting, headache, renal impairment, and low bone density are reported by patient groups as being associated with the drug; however, patients who provided input noted that most of these AEs are common to HIV treatment given a positive HIV status, and that they are manageable.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

APPENDIX 2: LITERATURE SEARCH STRATEGY

OVERVIEW Interface: Ovid Databases: Embase 1974 to present MEDLINE Daily and MEDLINE 1946 to present MEDLINE In‐Process & Other Non‐Indexed Citations Note: Subject headings have been customized for each database. Duplicates between databases were removed in Ovid. Date of Search: March 31, 2016 Alerts: Bi‐weekly search updates until July 20, 2016 Study Types: randomized controlled trials Limits: No date or language limits were used Conference abstracts were excluded SYNTAX GUIDE / At the end of a phrase, searches the phrase as a subject heading .sh At the end of a phrase, searches the phrase as a subject heading MeSH Medical Subject Heading fs Floating subheading exp Explode a subject heading * Before a word, indicates that the marked subject heading is a primary topic; or, after a word, a truncation symbol (wildcard) to retrieve plurals or varying endings # Truncation symbol for one character ? Truncation symbol for one or no characters only adj Requires words are adjacent to each other (in any order) adj# Adjacency within # number of words (in any order) .ti Title .ab Abstract .ot Original title .hw Heading word; usually includes subject headings and controlled vocabulary .kf Author keyword heading word (MEDLINE) .kw Author keyword (Embase) .pt Publication type .po Population group [PsycInfo only] .rn CAS registry number .nm Name of substance word pmez Ovid database code; MEDLINE In‐Process & Other Non‐Indexed Citations, MEDLINE Daily and Ovid MEDLINE 1946 to Present oemezd Ovid database code; Embase 1974 to present, updated daily

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

MULTI‐DATABASE STRATEGY Line # Search Strategy Results 1 "Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination"/ 131 2 (Truvada* or Emzavir* or Recovir EM or Teno Em or Tenvor EM or 438 Trenstad*).ti,ab,kf,ot,hw,rn,nm. 3 (731772‐45‐5 or "731772455").rn,nm. 0 4 1 or 2 or 3 529 5 (emtricitabin* or emtriva* or coviracil* or racivir* or Hui Er Ding* or Xin Luo Shu* or 15089 524W91 or "BW 1592" or "BW 524 w 91" or "BW 524 W91" or "BW 524W" or BW524W or BW524W91 or "DRG 0208" or DRG0208 or "psi 5004" or psi5004 or "HSDB 7337" or HSDB7337 or G70B4ETF4S or dOTFC or FTC).ti,ab,ot,kw,hw,rn,nm. 6 (143491‐57‐0 or "143491570").rn,nm. 5653 7 5 or 6 15090 8 (tenofovir* or GS 1278 or GS1278 or "GS 4331‐05" or GS433105 or HSDB 7165 or 24830 HSDB7165 or PMPA or OTT9J7900I or TDF or viread* or Agifovir* or Glonovir* or Ricovir* or Tenof or Tenofir* or Tenohop* or Tenolam* or Tenozet* or Tenvir* or Tenvor* or Viraday*).ti,ab,ot,kf,hw,rn,nm. 9 (379270‐37‐8 or 377091‐31‐1 or 147127‐20‐6).rn,nm. 10584 10 8 or 9 24830 11 7 and 10 10233 12 4 or 11 10279 13 12 use pmez 1627 14 *emtricitabine plus tenofovir disoproxil/ 420 15 (Truvada* or Emzavir* or Recovir EM or Teno Em or Tenvor EM or Trenstad*).ti,ab,kw. 443 16 14 or 15 794 17 *emtricitabine/ 644 18 (emtricitabin* or emtriva* or coviracil* or racivir* or Hui Er Ding* or Xin Luo Shu* or 8333 524W91 or "BW 1592" or "BW 524 w 91" or "BW 524 W91" or "BW 524W" or BW524W or BW524W91 or "DRG 0208" or DRG0208 or "psi 5004" or psi5004 or "HSDB 7337" or HSDB7337 or G70B4ETF4S or dOTFC or FTC).ti,ab,kw. 19 17 or 18 8505 20 *tenofovir disoproxil/ 1013 21 (tenofovir* or GS 1278 or GS1278 or "GS 4331‐05" or GS433105 or HSDB 7165 or 13807 HSDB7165 or PMPA or OTT9J7900I or TDF or viread or Agifovir or Glonovir or Ricovir or Tenof or Tenofir or Tenohop or Tenolam or Tenozet or Tenvir or Tenvor or Viraday).ti,ab,kw. 22 20 or 21 13880 23 19 and 22 3982 24 16 or 23 4325 25 conference abstract.pt. 2186750 26 24 not 25 2998 27 26 use oemezd 1610 28 13 or 27 3237 29 Pre‐exposure prophylaxis/ 960 30 Primary prevention/ 46916 31 pc.fs. 2130505 32 29 or 30 or 31 2149758

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

MULTI‐DATABASE STRATEGY Line # Search Strategy Results 33 32 use pmez 1098532 34 pre‐exposure prophylaxis/ or "prevention and control"/ or prevention/ or control/ or 558329 primary prevention/ or prophylaxis/ or protection/ or chemoprophylaxis/ or infection prevention/ or immunoprophylaxis/ or disease control/ or infection control/ 35 34 use oemezd 518058 36 (prevention or prevent or prevents or preventive or preventing or protecting or protect 3419669 or protects or protection or protective or chemoprophyla* or immunoprophyla* or prophyla* or preexposure or preventative).ti,ab,kw,kf. 37 PrEP.ti,ab,kw,kf. 6721 38 ((Pre or before or prior or advance) adj3 (expos* or risk or contact or intercourse or 92801 sex*)).ti,ab,kw,kf. 39 33 or 35 or 36 or 37 or 38 4408285 40 28 and 39 998 41 Randomized Controlled Trial.pt. 411023 42 Pragmatic Clinical Trial.pt. 274 43 exp Randomized Controlled Trials as Topic/ 196972 44 "Randomized Controlled Trial (topic)"/ 93773 45 Randomized Controlled Trial/ 809324 46 Randomization/ 155706 47 Random Allocation/ 148390 48 Double‐Blind Method/ 230781 49 Double Blind Procedure/ 129520 50 Double‐Blind Studies/ 224804 51 Single‐Blind Method/ 41296 52 Single Blind Procedure/ 21730 53 Single‐Blind Studies/ 43273 54 Placebos/ 262260 55 Placebo/ 284968 56 (random* or sham or placebo*).ti,ab,hw,kf,kw. 2601071 57 ((singl* or doubl*) adj (blind* or dumm* or mask*)).ti,ab,hw,kf,kw. 428966 58 ((tripl* or trebl*) adj (blind* or dumm* or mask*)).ti,ab,hw,kf,kw. 1182 59 or/41‐58 2650431 60 40 and 59 335 61 remove duplicates from 60 223

OTHER DATABASES PubMed A limited PubMed search was performed to capture records not found in MEDLINE. Same MeSH, keywords, limits, and study types used as per MEDLINE search, with appropriate syntax used. Trial registries Same keywords, limits used as per MEDLINE search. (Clinicaltrials.gov and others)

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

Grey Literature Dates for Search: March 2016 Keywords: Truvada, Pre‐exposure prophylaxis Limits: No date or language limits used

Relevant websites from the following sections of the CADTH grey literature checklist, “Grey matters: a practical tool for searching health‐related grey literature” (https://www.cadth.ca/grey‐matters) were searched:  Health Technology Assessment Agencies  Health Economics  Clinical Practice Guidelines  Drug and Device Regulatory Approvals  Advisories and Warnings  Drug Class Reviews  Databases (free)  Internet Search

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

APPENDIX 3: EXCLUDED STUDIES

Reference Reason for Exclusion Marazzo et al., 201535 Phase 2b study Van Damme et al., 201236 Outcome combined incidence of HIV‐1 and HIV‐2 Mutua et al., 201239 Intermittent dosing Baeten et al., 201658 Not a comparison of interest Buchbinder et al., 201459 Not a subgroup of interest Murnane et al., 201360

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

APPENDIX 4: DETAILED OUTCOME DATA

HIV‐1 Seroconversion

TABLE 19: HIV‐1 SEROCONVERSION IN THE IPREX STUDY AT DIFFERENT CUT‐OFF DATES; MODIFIED INTENTION‐ TO‐TREAT SET iPrEx FTC/TDF Placebo (n = 1,224) (n = 1,217) May 1, 2010 data cut‐off (primary analysis) Person‐years of follow‐up vvvv vvvv Participants with seroconversion events, n (%) 36 (2.9) 64 (5.3) Incidence per 100 person‐years (95% CI) 2.2a 3.8a Hazard ratio (95% CI) 0.56 (0.37 to 0.85) Relative risk reduction, % (95% CI) 44 (15 to 63) P value 0.005 July 31, 2010 data cut‐off (end of treatment) Person‐years of follow‐up vvvv vvvv Participants with seroconversion events, n (%) 48 (3.9) 83 (6.8) Incidence per 100 person‐years (95% CI) 2.3a 3.9a Hazard ratio (95% CI) 0.58 (0.40 to 0.84) Relative risk reduction, % (95% CI) 42 (18 to 60) P value 0.002 November 21, 2010 data cut‐off (end of treatment + 8 weeks) Person‐years of follow‐up vvvv vvvv Participants with seroconversion events, n (%) 52 (4.2) 85 (7.0) Incidence per 100 person‐years (95% CI) 2.4a 4.0a Hazard ratio (95% CI) 0.61 (0.43 to 0.86) Relative risk reduction, % (95% CI) 39 (14 to 57) P value 0.004

CI = confidence interval; FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; HIV = human immunodeficiency virus; NR = not reported. a Calculated by the CADTH Common Drug Review. Sources: iPrEx Clinical Study Report,4 iPrEx addendum.61

TABLE 20: SUBGROUP ANALYSIS ACCORDING TO SEX OF PRIMARY EFFICACY END POINT; MODIFIED INTENTION‐ TO‐TREAT SET Partners PrEP CDC TDF2 FTC/TDF Placebo FTC/TDF Placebo (n = 1,576) (n = 1,578) (n = 601) (n = 599) Primary analysis Person‐years of follow‐up 2,616 2,607 1,563 Participants with seroconversion events, n (%) 13 (0.8) 52 (3.3) 9 24 Incidence per 100 person‐years (95% CI) 0.50 (0.27 to 1.99 (1.49 1.2 3.1

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

Partners PrEP CDC TDF2 FTC/TDF Placebo FTC/TDF Placebo (n = 1,576) (n = 1,578) (n = 601) (n = 599) 0.85) to 2.62) Hazard ratio (95% CI) 0.25 (0.13 to 0.45) Relative risk reduction, % (95% CI) 75 (55 to 87) 62 (22 to 83) P value < 0.001 0.03 Sex Female Person‐years of follow‐up vvv vvv NR Participants with seroconversion events, n/n 9/566 (1.6) 28/619 (4.5) 7/280 (2.5) 14/277 (5.1) total (%) Incidence per 100 person‐years (95% CI) 0.95 (0.44 to 2.81 (1.87 NR NR 1.81) to 4.06) Hazard ratio (95% CI) 0.34 (0.16 to 0.72) 0.51 (0.19 to 1.78)a Relative risk reduction, % (95% CI) 66 (28 to 84)a 49 (–22 to 81) Male Person‐years of follow‐up vvvv vvvv NR Participants with seroconversion events, n/n 4/1,010 (0.4) 24/959 (2.5) 2/331 (0.6) 10/331 (3.0) total (%) Incidence per 100 person‐years (95% CI) 0.24 (0.07 to 1.49 (0.96 NR NR 0.61) to 2.22) Hazard ratio (95% CI) 0.16 (0.06 to 0.46) 0.20 (0.03 to 0.75)a Relative risk reduction, % (95% CI) 84 (54 to 94)a 80 (25 to 97)

CI = confidence interval; FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; NR = not reported. a Calculated by the CADTH Common Drug Review. Source: Partners PrEP Clinical Study Report,6 Baeten et al., 2012,7 Thigpen et al., 2012.8

Sexual Behaviour

TABLE 21: RECEPTIVE ANAL INTERCOURSE AND PROTECTED ANAL INTERCOURSE OVER TIME IN THE IPREX STUDY; SAFETY SET iPrEx Week FTC/TDF Placebo N at Study Mean (SE) Protected Anal N at Study Mean (SE) Protected Anal Week RAI Partners Intercourse (%) Week RAI Partners Intercourse (%) 0 1,251 12.2 (0.8) 51 1,248 11.2 (0.8) 50.4 12 1,118 7.2 (0.7) 74.5 1130 5.6 (0.5) 73 24 1,033 5.6 (0.5) 75.6 1,053 5.3 (0.5) 73 36 946 5.3 (0.5) 78.4 960 4.2 (0.3) 72.2 48 824 5.8 (0.7) 73.4 840 4.5 (0.5) 74.9 60 689 5 (0.5) 75.4 670 4.5 (0.5) 72.1 72 551 5 (0.8) 73.9 543 4.6 (0.7) 70.1 84 445 6.4 (1.1) 77.4 434 4.1 (0.5) 75.1 96 365 5.2 (0.7) 76.4 360 4.8 (0.9) 74

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

iPrEx Week FTC/TDF Placebo 108 269 5.1 (1) 78.2 271 3.9 (0.6) 76.3 120 157 5.7 (1.2) 75.6 147 4.6 (0.9) 83.3 132 72 3.5 (0.8) 74 63 5.7 (1.6) 83.6

FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; RAI = receptive anal intercourse; SE = standard error. Sources: iPrEx Clinical Study Report,4 Grant et al., 2010.5

TABLE 22: PROPORTION OF PARTICIPANTS REPORTING ANY UNPROTECTED SEX AND OUTSIDE SEX PARTNERS IN THE PREVIOUS MONTH IN THE PARTNERS PREP STUDY; SAFETY SET Partners PrEP Month N at Study Week Number (%) Reporting Number (%) With Unprotected Sex Outside Partners 0 4,758 1,271 (27) 407 (9) 3 4,565 789 (17) 414 (9) 6 4,492 640 (14) 444 (10) 12 3,950 511 (13) 485 (12) 18 3,090 356 (12) 379 (12) 24 2,168 204 (10) 292 (13) 30 867 56 (7) 111 (13) 35 118 11 (9) NR

NR = not reported. Source: US Food and Drug Administration Medical Review.28

Sexually Transmitted Infections

TABLE 23: PARTICIPANTS WITH SEXUALLY TRANSMITTED INFECTIONS BY VISIT IN THE IPREX STUDY iPrEx FTC/TDF Placebo Syphilis, n Week 24 173 165 Week 48 159 145 Week 72 108 111 Week 96 87 70 Warts, n Week 24 44 35 Week 48 37 34 Week 72 26 22 Week 96 15 19 Genital ulcer, n Week 24 18 18 Week 48 11 14 Week 72 6 11 Week 96 2 2

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

iPrEx FTC/TDF Placebo Gonorrhea, n Week 24 8 8 Week 48 4 6 Week 72 1 2 Week 96 1 1 Chlamydia, n Week 24 9 8 Week 48 0 2 Week 72 1 3 Week 96 0 1

FTC/TDF = emtricitabine/tenofovir disoproxil fumarate. Sources: iPrEx Clinical Study Report,4 Grant et al., 2010.5

TABLE 24: OUTSIDE SEXUAL PARTNERS AND INCIDENCE OF SEXUALLY TRANSMITTED INFECTIONS IN THE PARTNERS PREP STUDY; SAFETY SET Partners PrEP FTC/TDF Placebo (n = 1,579) (n = 1,584) Participants reporting outside sexual partner, n (%) 469 (29.7) 459 (28.9) P value versus placeboa 0.67 Participants reporting any STI, n (%) 76 (4.8) 85 (5.4) P value versus placebob 0.49

FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; STI = sexually transmitted infection. a P value calculated by chi‐squared test of proportions. b P value calculated via generalized estimating equations, using logistic link and robust standard errors to adjust errors for correlation within responses from the same participant over time. Sources: Partners PrEP Clinical Study Report,6 Baeten et al., 2012.7

TABLE 25: SEXUALLY TRANSMITTED INFECTION ADVERSE EVENTS IN THE CDC TDF2 STUDY; SAFETY SET CDC TDF2 FTC/TDF Placebo (n = 611) (n = 608) STI AE, n (%) Neisseria gonorrhoeae 28 (4.6) 18 (3.0) Chlamydia trachomatis 76 (12.4) 75 (12.3) Trichomonas vaginalis 20 (3.3) 18 (3.0) Genital herpes 28 (4.6) 35 (5.8) Sore genital ulcer 12 (2.0) 6 (1.0) AE = adverse event; FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; STI = sexually transmitted infection. Source: Thigpen et al., 2012.8

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

Adherence

TABLE 26: ADHERENCE TO STUDY DRUG IN THE IPREX STUDY; SAFETY SET iPrEx FTC/TDF Placebo (n = 1,251) (n = 1,248) Self‐reported pill use N vvvv vvvv Mean (SD), % 88.7 (18.1) vvvv vvvvvv Median (range), % vvvv vvvvv vvvvvv vvvv vvvvv vvvvvv FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; SD = standard deviation. Sources: iPrEx Clinical Study Report,4 Grant et al., 2010.5

TABLE 27: ADHERENCE TO STUDY DRUG IN THE PARTNERS PREP STUDY; SAFETY SET Partners PrEP FTC/TDF Placebo (n = 1,579) (n = 1,584) FTC/TDF or placebo FTC/TDF pill counts Number of participants assessed 1,565 1,570 % of expected bottles returned 98 98 % doses taken of dispensed 97 97 Bottles with ≥ 50% doses taken 99 99 Bottles with ≥ 75% doses taken 98 98 Bottles with ≥ 90% doses taken 93 92 Bottles with ≥ 95% doses taken 84 85 Self‐reported adherence Number of participants assessed vvvv vvvv Number of visits assessed vvvvvv vvvvvv Missed dose (%) vvvv vvvv vvvv vvvv Missed 2+ consecutive doses (%) vvvv vvv vvvv vvv

FTC/TDF = emtricitabine/tenofovir disoproxil fumarate. Sources: Partners PrEP Clinical Study Report,6 Baeten et al., 2012.7

Harms

TABLE 28: HARMS IN THE IPREX STUDY ACCORDING TO MANUFACTURER ANALYSIS; SAFETY SET iPrEx FTC/TDF Placebo (n = 1,251) (n = 1,248) AEs Participants with > 0 AEs, n (%) vvv vvvv vvv vvvv Common AEs Abdominal pain vv vvv vv vvv Depression vv vvv vv vvv Diarrhea vv vvv vv vvv 47

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

iPrEx FTC/TDF Placebo (n = 1,251) (n = 1,248) Dizziness v vvvv v vvvv Headache vv vvv vv vvv Nausea vv vvv v vvvv Pharyngitis vv vvv vv vvv Rash v vvvv v vvvv Respiratory tract infection v vvvv v vvvv Urethritis vv vvv vv vvv Upper respiratory tract infection vv vvv vv vvv Vomiting v vvvv v vvvv SAEs Participants with > 0 SAEs, n (%) vv vvv vv vvv WDAEs Participants with > 0 WDAEs, n (%) vv vvv vv vvv

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

APPENDIX 5: SUMMARY OF OPEN‐LABEL EXTENSION STUDY WITH PARTICIPANTS FROM MSM PrEP STUDIES

Objective To summarize the open‐label extension (OLE) study recruiting participants from three studies (ATN 082, iPrEx, and the US Safety Study) that evaluated the efficacy and safety of emtricitabine/tenofovir disoproxil fumarate (TDF/FTC) as a once‐daily pre‐exposure prophylaxis (PrEP) for human immunodeficiency virus type 1 (HIV‐1) in gay men or men who have sex with men (MSM).5

Findings Study Design The OLE study was a 72‐week study that enrolled patients who had completed the ATN 082, iPrEx, or US Safety Study randomized controlled trials (RCTs) to investigate PrEP uptake, adherence, and sexual practices in a manner more akin to clinical practice. Generally, the trial designs and the inclusion and exclusion criteria of the previous RCTs were similar to those of the OLE; however, the ATN 082 study included only men between 18 and 22 years of age, and the intervention in the US Safety Study consisted only of TDF. All participants were offered daily oral PrEP with FTC/TDF 200 mg/300 mg FDC along with a comprehensive package of prevention services such as counselling and contraception, among others, if they were HIV negative and had no symptoms of acute HIV infection. PrEP was deferred or interrupted for participants with an acute viral syndrome or any positive HIV test throughout the study until HIV test results were negative. Outcomes experienced by study participation were reported regardless of whether participants chose to take PrEP. Study visits were conducted every four weeks up until week 12, and every 12 weeks thereafter up to week 72. Participants were able to start PrEP at any time within the first 48 weeks of the extension phase.

Participants were eligible to enrol in the OLE if they met the following criteria:  Male at birth  Reported having had anal intercourse with men  Older than 18 years of age.

Efficacy was assessed by monitoring the incidence of HIV infection, HIV incidence as a function of dry blood spot TDF concentrations, HIV resistant strains, adherence, and sexual behaviour. Profile likelihood confidence intervals (CIs) were used because of the small number of infections in each dosing category. It was estimated that the concentration of drug associated with 90% protection had a relative risk of 0.10 compared with the group with no exposure to PrEP. Adjustments were made for non‐condom receptive anal intercourse (RAI), age, number of partners, history of syphilis, and enrolment site. Predictors of drug concentrations were assessed, by dosing category, with an ordinal logistic regression model, adjusted for study site and time on study. Comparisons of HIV incidence between the previous RCTs (ATN 082, iPrEx, and US Safety Study) and the OLE were assessed.

Adherence was assessed using tenofovir (TFV) blood plasma concentrations and dry blood spot emtricitabine (TDF) concentrations. Sexual behaviour was assessed based on patient self‐report, and data were analyzed using generalized estimating equations. Safety was assessed by monitoring treatment interruptions.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

Results A total of 1,678 (62%) of 2,680 eligible participants enrolled in the OLE study. The majority of the participants screened for inclusion were from the iPrEx trial (1,526; 90.9%). Seventy‐five (4.5%) tested positive for HIV at enrolment, leaving a total of 1,603 (95.5%) eligible to receive PrEP in the OLE. A total of 1,128 (70.4%) started PrEP at enrolment, 97 (6.1%) started PrEP within 48 weeks of enrolment, and 378 (23.6%) never started PrEP. Of the 1,225 who received PrEP, 1,033 (84.3%) completed the study, 36 (2.9%) exited early, and one (< 0.1%) died. Patient disposition is detailed in Table 29.

TABLE 29: PATIENT DISPOSITION OLE Study Eligible to enrol, Na 2,680 ANT082 68 iPrEx 2,336 US Safety Study 271 Screened, N 1,678 ANT082 46 iPrEx 1,526 US Safety Studyb 106 HIV‐1–infected at baseline, n 75 Followed for seroconversion, n (%) 1,603 (100) Started PrEP at enrolment 1,128 (70) Started PrEP after enrolment 97 (6) Never started PrEP 378 (24) Completed the study, n (%) 1,345 (84) Started PrEP at enrolment 945 (59) Started PrEP after enrolment 88 (5) Never started PrEP 312 (19) Discontinuation for those on PrEP, n (%) Death 1 (< 1) Lost contact with participant 65 (5) Participant relocated 75 (6) Exited early 36 (3) Incarcerated 2 (< 1) Other reason 3 (< 1)

OLE = open‐label extension; PrEP = pre‐exposure prophylaxis. a Enrolment numbers are people who were HIV‐negative when they left the previous study. b Participants enrolled in Boston and San Francisco. Source: Grant et al.5

Of the 1,603 eligible to receive PrEP, 265 (17%) were white, 125 (8%) were black, 73 (5%) were Asian, and 1,094 (72%) were Latino. Those who enrolled in the OLE tended to be older (mean age 28 years versus 26 years, P < 0.0001), were more likely to report non‐condom RAI (60% versus 55%, P = 0.03), and were more likely to have a history of syphilis (15% versus 10%, P = 0.001) or herpes (38% versus 30%, P < 0.0001) compared with those who did not enroll in the OLE. A similar number of participants from the placebo and the treatment groups from the previous studies participated in the OLE. Of the 446 participants who had been in the treatment group in the previous iPrEx trial, those who had detectable 50

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA drug were more likely to enroll in the OLE than those without detectable drug (69% versus 57%, P = 0.02). Patient baseline characteristics are detailed in Table 30.

TABLE 30: BASELINE CHARACTERISTICS Characteristic OLE Study FTC/TDF (n = 1,225) Age, n (%) 18 to 24 years 247 (20) 25 to 29 years 315 (26) 30 to 39 years 394 (32) ≥ 40 years 269 (22) Race, n (%) White 265 (17) Black 125 (8) Asian 73 (5) Latino 1,094 (72) Country, n (%) USA 224 (18) Brazil 192 (16) Peru 562 (46) Ecuador 153 (12) South Africa 40 (3) Thailand 54 (4) Education Level, n (%)a Less than secondary 264 (22) Completed secondary 387 (32) Post‐secondary 566 (46) Alcohol use, n (%) < Once a month 103 (8) 1 to 4 on days when drinking 403 (33) ≥ 5 on days when drinking 250 (20) Refused to answer or did not know 469 (38) Methamphetamine use, n (%)a No 1,190 (97) Yes 26 (2) Cocaine use, n (%)a No 1,070 (87) Yes 101 (8) Reported non‐condom receptive anal intercourse at OLE entry, n (%) No 809 (66) Yes 416 (34) Transgender, n (%) No 1,085 (89)

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

Characteristic OLE Study FTC/TDF (n = 1,225) Yes 140 (11) Known HIV‐positive partner, n (%) No 1,083 (88) Yes 142 (12) Syphilis rapid plasma regain at entry, n (%) No 1,028 (84) Yes 197 (16) Herpes simplex virus‐2, n (%) No 613 (50) Yes 612 (50) Gonorrheaa by urine PCR, n (%)a No 1,186 (97) Yes 25 (2) Randomized experience a Placebo 550 (45) Active, no drug at week 8 65 (5) Active, drug at week 8 155 (13)

FTC/TDF = emtricitabine/tenofovir disoproxil fumarate; HIV = human immunodeficiency virus; OLE= open‐label extension; PCR = polymerase chain reaction. a Data missing for some participants. Source: Grant et al.5

Efficacy A total of 41 participants had HIV‐1 seroconversion in the OLE study, of which 13 did not receive PrEP (2.6 infections per 100 person‐years; 95% CI, 1.5 to 4.5), and 28 of those on FTC/TDF (1.8 infections per 100 person‐years, 95% CI, 1.3 to 2.6). Of those receiving FTC/TDF, the HIV incidence was 49% (95% CI, –1 to 74) lower than among those who did not receive PrEP, when adjusted for the higher risk sexual behaviour at baseline among participants using PrEP, and 36% (95% CI, –24 to 67) lower if not adjusted. Considering only participants who participated in the iPrEx trial, there was a reduction of 53% (95% CI, 26 to 70) in HIV incidence when compared with the placebo group in the iPrEx trial (3.93 infections per 100 person‐years), and a reduction of 51% (95% CI, 23 to 69) in HIV incidence when compared with the time between the previous randomized trial and the OLE (3.81 infections per 100 person‐years).

The relationship between HIV incidence and dried blood spot TDF was assessed. The authors indicated that the results suggested a strong association between HIV incidence and TDF levels and reported no infections at visits where TDF concentrations were 700 fmol per punch or greater (associated with a regimen of four to seven tablets per week). The study also reports that a concentration of TDF from dry blood spots of 611 fmol per punch (95% CI, 216 to 1,006) (associated with a regimen of two to three tablets per week) achieved a 90% risk reduction of HIV acquisition. There was only one participant taking PrEP with a reported case of HIV resistance to emtricitabine in the OLE. The results detailing the association between HIV incidence and TDF levels are presented in Table 31.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

TABLE 31: EFFECT OF TENOFOVIR DIPHOSPHATE IN DRIED BLOOD SPOT ON HIV INFECTION BLQ LLOQ to < 350 350 fmol to 699 700 fmol to ≥ 1,250 fmol per punch fmol per punch 1,249 fmol per fmol per punch punch Estimated dose None < 2 2 to 3 4 to 6 7 (tablets per week) Follow‐up (% of 25 26 12 21 12 visits) HIV infections, n 18 9 1 0 0 Person‐years per 384 399 179 316 181 infection HIV incidence (95% 4.70 (2.99 to 2.25 (1.19 to 0.56 (0.00 to 2.50) 0.00 (0.00 to 0.00 (0.00 to CI) 7.76) 4.79) 0.61) 1.06) HR versus previous 1.55 (0.88 to 0.69 (0.32 to 0.19 (0.01 to 0.88) 0.00 (0.00 to 0.00 (0.00 to placebo (95% CI)a 2.56) 1.32) 0.25) 0.50) HR versus 1.25 (0.60 to 0.56 (0.23 to 0.16 (0.01 to 0.79) 0.00 (0.00 to 0.00 (0.00 to concurrent off‐PrEP 2.64) 1.31) 0.21) 0.43) (95% CI)b

BLQ = below limit of quantification; CI = confidence interval; HIV = human immunodeficiency virus; HR = hazard ratio; LLOQ = lower limit of quantification; PrEP= pre‐exposure prophylaxis. Note: Drug concentration measurements were not available for 5% of visits. a Adjusted for study site. b Adjusted for study site, age, number of sexual partners, non‐condom receptive anal intercourse, and syphilis. Source: Grant et al.5

Treatment adherence was assessed based on blood plasma tenofovir concentrations for 305 patients at week four, 851 patients at week eight, and 33 patients at week 12. Thirty‐six participants were not assessed for treatment adherence. Tenofovir (TFV) was detected in 71% of participants, and detection varied by region, ranging from 62% of participants in Ecuador to 83% of participants in the US. The authors reported a similar proportion of patients with detectable TFV in blood plasma in the OLE compared with the first eight weeks of the previous iPrEx trial. Drug concentrations based on dried blood spots were higher among those who had more years of education; were older participants; had had non‐condom receptive anal intercourse, more sexual partners, a history of syphilis or herpes, any HIV‐positive sexual partner, or lower estimated creatinine clearance and was not associated with alcohol use, methamphetamine use, or cocaine use.

Participants receiving PrEP and participants not receiving PrEP reported similar decreases in sexual behaviours (i.e., total number of sexual partners, RAI and insertive anal intercourse) during the OLE study. The percentage of patients engaging in non‐condom RAI decreased from 34% to 25% for those taking PrEP, and from 27% to 20% for those not taking PrEP. The incidence of syphilis was similar for those taking PrEP compared with those not taking PrEP, with a hazard ratio of 1.35 (95% CI, 0.83 to 2.19, 7.2 infections per 100 patient‐years versus 5.4 infections per 100 patient‐years).

Safety Treatment was interrupted 380 times for 365 participants for reasons other than loss to follow‐up, completion of the study, or HIV infection. Reasons for treatment interruption included participant preference (40%), adverse events (24%), effects of significant but unrelated comorbidities (10%), relocation of travel (14%) and other (14%), which included suspected acute HIV infection (2%) and sexual behaviour warranting a post‐exposure prophylaxis (PEP) (4%). Gastrointestinal symptoms such as 53

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA nausea or abdominal pain were the most common symptoms requiring study drug interruption. In total, there were three cases of increased creatinine levels, all of which returned to normal after study drug interruptions and none of which returned upon treatment continuation.

Limitations There are many limitations in the OLE study, the main being that it was an open‐label (OL) trial and there was the lack of a consistent and appropriate comparator group against which to evaluate the outcomes of interest in the review. The OL trial design, in which both the investigators and the patients are unblinded to treatment allocation, may have had an impact on subjective outcomes such as sexual behaviour as it was assessed in this study. The comparator groups used in this study were variable depending on the outcome measures assessed, and the baseline characteristics of the participants in the comparator groups were not presented in the study. Consequently, the long‐term comparative efficacy and safety of FTC/TDF as PrEP remains uncertain. In addition, given that the patients who received FTC/TDF as PrEP in this study were self‐selected from the cohort of patients participating in the previous RCTs (for example, compared with the RCTs, a high proportion of participants were Latino, participants tended to engage in riskier sexual behaviour, and tended to be more adherent to treatment), the generalizability of the results of this study should be made with caution. Finally, it is uncertain how the decrease in the percentage of patients engaging in risky sexual behaviour during the study period may have impacted the incidence of HIV reported.

Summary In general, OL trial designs such as the one presented here may be more reflective of clinical practice in terms of the level of treatment adherence and the sample population enrolled. The results from the OLE study suggest a reduction in the incidence of HIV seroconversion with the use of TDF/FTC and a dose‐ efficacy relationship between TDF levels and HIV incidence. Treatment with TDF/FTC as PrEP was generally well tolerated. Results suggest a similar decrease in the total number of sexual partners and in both non‐condom RAI and insertive anal intercourse for those participating in the trial, regardless of exposure to TDF/FTC as PrEP. Caution is required when interpreting the results of the OLE study, given the key limitations.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

APPENDIX 6: SUMMARY OF THE PILOT PHASE OF THE PROUD STUDY

Objective To summarize the pilot phase of the ongoing PROUD study, which evaluated the effectiveness and safety of emtricitabine/tenofovir disoproxil fumarate (TDF/FTC) 200 mg/300 mg fixed‐dose combination (FDC) as a once‐daily pre‐exposure prophylaxis (PrEP) for human immunodeficiency virus type 1 (HIV‐1) in gay men or men who have sex with men (MSM).40

Findings Study Design PROUD is a phase 4, open‐label (OL), randomized controlled trial (RCT) conducted in 13 sexual health clinics in the UK in which neither patients nor investigators were blinded to treatment allocation. All participants were offered a comprehensive package of prevention services such as counselling and contraception, among others. Patients were randomized 1:1 to either an immediate treatment arm (patients received FTC/TDF 200 mg/300 mg FDC once daily immediately at enrolment) or a deferred treatment arm (patients received FTC/TDF 200 mg/300 mg FDC once daily one year after enrolment). Randomization was done via Web‐based access to a central computer‐generated list with variable block sizes (four, six, and eight) and was stratified by study site. To better simulate a public health PrEP program, no screening visits took place, and data on sexually transmitted infections (STIs) that were documented at other clinics or non‐study visits were also collected. Follow‐up visits occurred quarterly for the duration of the two‐year trial. PROUD was designed with a sample size of 5,000 participants, powered to detect a 50% reduction in HIV incidence from 2.5 to 1.25 infections per 100 person‐years. For the pilot phase, participants were included based on the time to accrue and retain 10% of the planned sample size (n = 500). Data from the pilot phase analysis are summarized in this report.

Patients were eligible for inclusion if they met the following criteria:  Previously attended the enrolling clinic  Screened for HIV and other STIs  Tested HIV‐negative four weeks prior to or on the day of enrolment  Male at birth  Aged 18 years and older  Had had anal intercourse without a condom in the previous 90 days and were likely to have anal intercourse without a condom in the next 90 days.

Patients were excluded from the study if they met the following criteria:  Diagnosed with acute viral illness possibly due to HIV seroconversion  Contraindication to TDF or FTC  Treated for hepatitis B

The primary efficacy outcome was the time to accrual of 500 participants and retention. Secondary outcomes included the incidence of HIV infection during the deferral period, adherence, and risk compensation related to sexual practices. Adherence was measured by assessing overall prescriptions of the study drug, and risk compensation was measured using a questionnaire related to sexual behaviour at baseline and at one year. The number of different anal sex partners at one year was compared

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA between groups using a stratified trend with respect to baseline anal sex partners at enrolment. Safety was assessed by monitoring adverse events (AEs) and serious adverse events (SAEs).

All analyses included all participants according to their randomized allocation (intention‐to‐treat [ITT]) apart from the exclusion of individuals with a reactive HIV result at enrolment in the analysis of HIV incidence (modified intention‐to‐treat [mITT]). The authors also noted that a 90% confidence interval (CI) was reported instead of a 95% CI, as they were mainly interested in the lower confidence limit (i.e., the minimum effectiveness).

The authors noted that because the analysis was based on a pilot phase, it was unlikely to show the effectiveness of PrEP; therefore, the data were initially monitored by a single independent expert who was not masked to allocation.

Results Of the enrolled 544 participants, 275 were randomized to the immediate treatment group and 269 were randomized to the deferred treatment group. Of the 275 patients in the immediate treatment group, two (0.7%) were HIV‐positive at enrolment and five (1.8%) did not undertake an HIV test after enrolment. The remaining 268 participants contributed to the analysis of HIV‐1 seroconversion, of which three (1.1%) withdrew, 17 (6.2%) were lost to follow‐up, and one (0.4%) died. Of the 269 patients in the deferred treatment group, one (0.4%) was HIV‐positive at enrolment and 13 (4.8%) did not undergo an HIV test after enrolment. The remaining 255 participants contributed to the analysis of HIV‐1 seroconversion, of which four (1.5%) withdrew and 16 (5.9%) were lost to follow‐up. Patient disposition is detailed in Table 32.

TABLE 32: PATIENT DISPOSITION PROUD Immediate treatment group Deferred treatment group Enrolled, Na 544 Randomized, N 275 269b HIV‐1–infected at enrolment, n (%) 2 (0.7) 1 (0.4) Not tested for HIV at enrolment, n (%) 5 (1.8) 13 (4.8) Followed for seroconversion, n (%) 268 (97) 255 (95) Discontinuation, n (%) Death 1 (0.4) 0 Loss to follow‐upc 17 (6.2) 16 (5.9) Withdrew consent 3 (1.1) 4 (1.5) HIV status assessed, n (%)d 247 (90) 235 (87)

HIV = human immunodeficiency virus. a 19 pairs of partners were assigned to the same group (14 to the immediate treatment group and five to the deferred treatment group) including six pairs (all assigned to the immediate treatment group) that were not enrolled concurrently. b One participant received immediate pre‐exposure prophylaxis in error despite being allocated to the deferred treatment group and was included in the deferred treatment group for analyses. c Reasons for loss to follow‐up included unable to contact, moved away, and non‐attendance as no longer at risk. d HIV status ascertained after a confirmed HIV‐positive or HIV‐negative test (48 weeks or after October 13, 2014). Source: McCormack et al., 2016.40

The included population was mostly white and was born outside the UK. The majority of participants disclosed no partners and had been diagnosed with a STI in the previous 12 months. Missing baseline 56

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA characteristic data were similar in the immediate treatment group compared with the deferred treatment group. The most common missing characteristics being chemsex use (seven versus eight), history of STI (13 versus 10), previous HIV tests (10 versus 10), and use of post‐exposure prophylaxis (PEP) (15 versus 15) in the immediate treatment group versus the deferred treatment group, respectively. Patient baseline characteristics are detailed in Table 33 and were similar between treatment groups.

TABLE 33: BASELINE CHARACTERISTICS PROUD Immediate treatment group Deferred treatment group Age, median (IQR) 35 (30 to 43) 35 (29 to 42) Ethnicity, n (%) White 220 (81) 219 (83) Black 14 (5) 15 (6) Asian 11 (4) 10 (4) Other 28 (10) 21 (8) University degree, n (%) 161 (59) 166 (62) Unemployed, n (%) 24 (9) 20 (8) Born outside the UK, n (%) 110 (40) 107 (40) Relationship status, n (%) Partner, living together 87 (32) 73 (27) Partner, living separately 40 (15) 46 (17) No partner 146 (53) 147 (55) Circumcised, n (%) 77 (28) 79 (30) Chemsex in the previous 90 days,a n (%) 115 (43) 116 (45) STI diagnosed in previous 12 months, n (%) Any 164 (63) 167 (65) Bacterialb 150 (58) 155 (60) Rectal gonorrhea or chlamydia 89 (34) 83 (32) Number of HIV tests in previous 12 months, 3 (2 to 4) 3 (2 to 4) median (IQR) Used PEP in previous 12 months, n (%) 91 (35) 93 (37)

HIV = human immunodeficiency virus; IQR = interquartile range; PEP = post‐exposure prophylaxis; STI = sexually transmitted infection. a Use of either gamma‐hydroxybutyrate, 4‐methylmethcathinone, or methamphetamine to facilitate or enhance sex. b Gonorrhea, chlamydia, or syphilis. Source: McCormack et al., 2016.40

Efficacy Three HIV infections occurred in the immediate treatment group compared with 20 in the deferred treatment group. The authors noted that the three infections that occurred in the immediate treatment group were attributable to the lack of adherence to the study drug. HIV incidence was reported to be 1.2 cases per 100 patient‐years (90% CI, 0.4 to 2.9) in the immediate treatment group compared with 9.0 cases per 100 patient‐years (90% CI, 6.1 to 12.8) in the deferred treatment group. The difference in the incidence of HIV‐1 between the two groups suggested a relative rate reduction of 86% (90% CI, 64 to 96; P = 0.0001) and a relative rate difference of 7.8 cases per 100 patient‐years (90% CI, 4.3 to 11.3) in favour of the immediate treatment group. The authors suggested that, based on the results from this 57

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA trial, 13 men (90% CI, 9 to 23) in this study would have needed to receive PrEP for one year to avert one HIV infection.

All five participants (including the two individuals who had HIV at enrolment) in the immediate treatment group who had HIV infection were tested for resistance. Two of the three participants with a reactive test at enrolment or the four‐week visit developed mutations thought to be due to exposure to FTC. No resistance was detected in the two other participants with later infections. The authors noted that the absence of resistance was not surprising given their apparent non‐adherence to PrEP. No participants had mutations associated with TDF treatment.

A total of 271 (99%) participants in the immediate treatment group and 263 (98%) in the deferred treatment group completed questionnaires related to sexual behaviour in the previous 90 days at baseline. Two hundred and twelve (77%) participants in the immediate treatment group and 194 (74%) in the deferred treatment group completed questionnaires at one year. The total number of different anal sex partners varied widely from baseline to one year; however, the authors reported no significant difference between groups. A larger proportion of participants in the immediate treatment group reported receptive anal sex with 10 or more partners without a condom compared with the deferred treatment group (21% versus 12%; P = 0.03).

One hundred and fifty‐two (57%) of participants in the immediate treatment group compared with 124 (50%) in the deferred treatment group were diagnosed with at least one bacterial STI. The most common STIs were gonorrhea and chlamydia. After adjusting for the number of STI screening tests, the authors reported no statistically significant difference in the incidence of any individual bacterial STIs (odds ratio: 1.07; 90% CI, 0.78 to 1.46; P = 0.74) between the immediate and deferred treatment groups. Bacterial STIs are detailed in Table 34.

TABLE 34: BACTERIAL SEXUALLY TRANSMITTED INFECTIONS PROUD Immediate Deferred Unadjusted Adjusted Odds Ratio P Value Treatment Group Treatment Group Odds Ratio (90% CI)a Any STI 152/265 124/247 1.33 1.07 (0.78 to 1.46) 0.74 Gonorrheab 103/261 89/242 1.12 0.86 (0.62 to 1.20) 0.46 Chlamydia b 77/261 54/242 1.46 1.27 (0.89 to 1.80) 0.27 Syphilis 30/263 22/247 1.32 1.29 (0.79 to 2.10) 0.39 Rectal gonorrhea or 93/258 77/238 1.18 1.00 (0.72 to 1.38) 0.99 chlamydia

CI = confidence interval; STI = sexually transmitted infection. Note: Infections diagnosed during deferral phase of follow‐up; analysis based on participants with at least one screen. a Adjusted for the number of screens for specific infection. b Detected in throat, urethra, or rectum. Source: McCormack et al., 2016.40

Safety AEs were assessed only in the immediate treatment group during the deferral phase. A total of 21 (8%) of the 275 participants in the immediate treatment group experienced an interruption or missed doses due to AEs, of which 20 restarted treatment with the study drug. Three of the 21 participants experienced elevated creatinine concentration leading to treatment interruption, of which two had

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA comorbidities and were taking concomitant prescription drugs and one was thought to be due to recreational drug use. The most common AEs were nausea, headache, and arthralgia. A total of 29 SAEs (including one death) were reported in 27 participants; however, none were deemed attributable to the study drug.

Limitations There are many limitations related to the PROUD study. The first is that the results presented are based on the pilot phase of the study with an arbitrary cut‐off of 10% of the planned sample size. Although a statistically significant difference was found in some outcomes including HIV incidence, the study may not have been adequately powered to detect a difference between the two treatment groups for other outcomes of interest such as safety. Further, the early termination of the study may have increased the probability of experiencing a type I error. The trial consisted of an open‐label (OL) design, whereby both the investigators and the patients were unblinded to treatment allocation; this may have an impact on subjective outcomes such as adherence and risk compensation. The absence of adherence data and the lack of sexual behaviour data are other important limitations, as they limit the assessment of risk compensation behaviour associated with adherence and the use of PrEP. The higher‐than‐expected incidence of HIV for the included sample in this trial may not be representative of the general population. Finally, the study was conducted in the UK, where standard clinical practice may differ from that which is seen in Canada.

Summary In general, OL trial designs such as the one presented here may be more reflective of clinical practice in terms of the level of treatment adherence and the sample population enrolled. The results of the pilot phase of the ongoing PROUD study suggest that immediate treatment with FTC/TDF as PrEP was associated with a reduction in the incidence of HIV infection compared with deferred treatment. There were no significant differences in number of sexual partners or STIs for those taking FTC/TDF as PrEP compared with those not receiving PrEP; however, a larger proportion of participants reported receptive anal sex with 10 or more partners without a condom in the immediate treatment group compared with the deferred treatment group. Overall, treatment with FTC/TDF as PrEP was generally well tolerated. The results of this study should be interpreted with caution given the high‐risk nature of the sample of participants enrolled and given that the results are based on data derived from the pilot phase of the study, which may not have adequate power to detect differences between groups for some outcomes of interest.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

APPENDIX 7: SUMMARY OF THE DOUBLE‐BLIND PHASE OF THE IPERGAY STUDY

Objective To summarize the double‐blind (DB) phase of the ongoing IPERGAY study, which evaluated the efficacy and safety of FTC/TDF for on‐demand, pre‐exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) type 1 in gay men or men who have sex with men (MSM).38

Findings Study Design IPERGAY was a phase 3, multi‐centre, DB, placebo‐controlled, randomized controlled trial (RCT) conducted in six centres in France and one centre in Canada. Participants were randomized 1:1 to either an active treatment group or a placebo group. All participants were offered a comprehensive package of prevention services such as counselling and contraception, among others. Patients in the active treatment group received tenofovir disoproxil fumarate (TDF) (300 mg) and emtricitabine (FTC) (200 mg) fixed‐dose combination (FDC) on‐demand therapy, in which patients took a loading dose of two pills with food two to 24 hours before sex, followed by a third pill 24 hours after the loading dose and a fourth pill 48 hours after the loading dose. Randomization was done via a fixed‐size block of four and was stratified by country. Follow‐up visits were scheduled at weeks four and eight after enrolment and every eight weeks thereafter for the duration of the four‐year trial. The authors reported that 64 HIV seroconversion events would provide 80% power to detect a 50% relative reduction in the incidence of HIV‐1 infection at a two‐sided alpha level of 0.05. Therefore, a sample size of 1,900 participants with a 12‐ to 36‐month follow‐up would be required to achieve the target number of events, given that the expected HIV incidence in the placebo group was three cases per 100 patient‐years and considering a loss to follow‐up of 15 participants per 100 patient‐years. As per request from the data and safety monitoring board, an unblinded interim analysis was conducted; consequently, the placebo group was discontinued and all the study participants were offered on‐demand PrEP. The study was ongoing as an OL study at the time of this review; data from the DB phase of the study were summarized for this report.

Patients were eligible to participate in the DB phase if they met the following criteria:  HIV‐negative  Aged 18 years and older  MSM or transgender females who have sex with men  At high risk for HIV infection (defined as unprotected anal intercourse with at least two partners in the previous six months)

Patients were excluded from participating in IPERGAY if they met the following criteria:  Tested positive for hepatitis B antigen  Chronic hepatitis C infection  Creatinine clearance < 60 mL/minute  Alanine aminotransferase level > 2.5 times the upper limit of the normal range  Glycosuria or proteinuria > 1+ on urine dipstick testing

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

The primary efficacy end point was assessed by monitoring the incidence of HIV‐1 infection. Genotypic testing was also performed at the time of diagnosis to assess resistant HIV strains. Adherence to the study drug was assessed by pill counts at every visit, by plasma drug concentrations for the first 113 participants enrolled in the study, and at the most recent sexual intercourse by means of computer‐ assisted interviews. Safety was assessed by monitoring adverse events (AEs).

All participants who received at least one dose of the study drug were included in the safety analyses. AEs were recorded at each visit regardless of their association with the treatment. All participants who were randomized were included in the intention‐to‐treat (ITT) analysis. A modified intention‐to‐treat (mITT) analysis approach was used for the HIV‐1 seroconversion end point, in which participants were excluded if they had been HIV‐positive before receiving any study drug, if they were lost to follow‐up or withdrew consent between randomization and enrolment, and did not receive any study drug. The Kaplan–Meier method was used to estimate the cumulative probability of HIV‐1 infection per group, and used the log‐rank test to perform between‐group comparisons. Probit and binomial mixed models were used to assess sexual behaviour in the two study groups.

Results Of the 445 participants enrolled, 206 were randomized to the treatment group and 208 were randomized to the placebo group. Of the 206 participants in the treatment group, 199 (96.6%) received intervention, four (1.9%) withdrew consent, two (1%) were lost to follow‐up, and one (0.5%) acquired HIV before receiving the study drug. Of the 208 patients in the placebo group, 201 (96.6%) received intervention, two (1%) withdrew consent, three (1.4%) were lost to follow‐up, and two (1%) acquired HIV before receiving placebo. A total of 49 (12%) participants discontinued follow‐up during the trial, of whom 23 (12%) were in the treatment group and 26 (13%) were in the placebo group, resulting in a total of 431.3 person‐years of follow‐up. The median duration of follow‐up was 9.3 months (interquartile range [IQR] 4.9 to 20.6). Patient disposition is detailed in Table 35.

TABLE 35: PATIENT DISPOSITION IPERGAY TDF/FTC Placebo Enrolled, N 445 Randomized, N 414 Allocation, N 206 208 Received intervention, N 199 201 Did not receive intervention, n (%) 7 (4) 7 (3) Withdrew consent 4 (2) 2 (1) Lost to follow‐up 2 (1) 3 (1) Acquired HIV‐1 infection 1 (1) 2 (1) Discontinuation, n (%) 23 (12) 26 (13) Loss to follow‐up 6 (3) 6 (3) Withdrew consent 14 (7) 17 (8) Other 3 (2) 3 (1)

TDF/FTC = tenofovir disoproxil fumarate/emtricitabine; HIV = human immunodeficiency virus. Source: Molina et al.38

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

Baseline characteristics of participants are detailed in Table 36 and were similar between treatment groups. All participants were male (100%), with a median age of 35 years in the treatment group and 34 in the placebo group. The majority of participants (72% in the treatment group and 74% in the placebo group) declared their relationship status as “not in a couple.” The median number of sexual partners in the previous two months (eight partners) and the median number of episodes of sexual intercourse in the previous four weeks (10 episodes) was the same in both groups. The proportion of participants reporting consumption of more than five alcoholic drinks per day in the previous month and recreational drug use were 25% and 43%, respectively, in the treatment group and 21% and 46%, respectively, in the corresponding placebo group.

TABLE 36: BASELINE CHARACTERISTICS

Characteristics IPERGAY TDF/FTC (N = 199) Placebo (N = 201) Male, n (%) 199 (100) 201 (100) Age in years, median (IQR) 35 (29 to 43) 34 (29 to 42) Age group in years, n (%) 18 to 24 31 (16) 27 (13) 25 to 29 26 (13) 30 (15) 30 to 39 72 (36) 73 (36) 40 to 49 50 (25) 55 (27) ≥ 50 20 (10) 16 (8) White race, n (%)a 188 (94) 178 (89) Relationship, n (%) Not in a couple 144 (72) 149 (74) In a couple with HIV‐1–positive partner 19 (10) 13 (6) Other 36 (18) 39 (19) Post‐secondary education, n (%) 146 (73) 141 (70) > 5 alcoholic drinks per day in previous month, n (%) 49 (25) 42 (21) Use of recreational drugs, n (%)b 85 (43) 92 (46) Site of enrolment, n (%) France Paris 96 (48) 105 (52) Lyon 47 (24) 36 (18) Nice 13 (7) 18 (9) Tourcoing 13 (7) 14 (7) Nantes 9 (5) 6 (3) Montreal 21 (11) 22 (11) Sexual risk factors at screening, median (IQR) Median number of partners in previous two months 8 (5 to 17) 8 (5 to 16) Median number of episodes of sexual intercourse in previous four 10 (6 to 18) 10 (5 to 15) weeks Circumcised, n (%) 38 (19) 41 (20)

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

Characteristics IPERGAY TDF/FTC (N = 199) Placebo (N = 201) STI diagnosed at screening, n (%)c 49 (25) 62 (31) HBV, n (%) Susceptible 46 (23) 38 (19) Immune from natural infection 18 (9) 31 (15) Immune from vaccination 135 (68) 132 (66)

HBV = hepatitis B virus; HIV = human immunodeficiency virus; IQR = interquartile range; STI = sexually transmitted infection; TDF/FTC = tenofovir disoproxil fumarate/emtricitabine. a Race was reported by investigators. b Recreational drugs that were reported in the previous 12 months included ecstasy, crack cocaine, cocaine, crystal, speed, and gamma‐hydroxybutyric acid or gamma‐butyrolactone. c Infections included syphilis, gonorrhea, and chlamydia. Source: Molina et al.38

Efficacy Based on the mITT population, 16 HIV‐1 seroconversions occurred during the study, two of which occurred in the treatment group and 14 of which occurred in the placebo group. The incidence was 0.91 per 100 person‐years in the treatment group and 6.60 per 100 person‐years in the placebo group, resulting in a relative reduction of 86% (95% confidence interval [CI], 40 to 98; P = 0.002) in favour of the treatment group. Of the two HIV‐1 seroconversion events in the FTC/TDF group, the authors reported that the patients had not been adherent to the intervention based on pill counts and on plasma drug concentrations. The authors also noted that none of the 16 HIV‐1 seroconversions that occurred during the study were drug‐resistant strains.

Treatment adherence measured by pill counts suggested that participants took a median of 15 pills (IQR, 11 to 21) per month in the treatment group compared with a median of 15 pills (IQR, 9 to 21) in the placebo group. Treatment adherence as measured by tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) plasma levels in a subset of patients found that participants in the treatment group had an 86% and 82% rate of detection of TDF and FTC, respectively. Finally, according to self‐report measures of treatment adherence, 28% of participants had not taken treatment or placebo, 29% had taken a suboptimal regimen, and 43% had taken the dose correctly. Adherence to the intervention using patient self‐report based on the last sexual intercourse is detailed in Table 37.

Sexual behaviour was reported as unchanged throughout the study period when compared with baseline. There were no statistically significant differences between the treatment group and placebo group in the total number of episodes of sexual intercourse in the four weeks before visits, the proportion of episodes of receptive anal intercourse without condoms, and in the proportion of episodes of anal sex without condoms during the most recent sexual intercourse. There was a small but statistically significant difference in the number of sexual partners in the previous two months in the placebo group compared with the treatment group (7.5 versus 8, respectively; P = 0.001). The number of new sexually transmitted infections (STIs) in the treatment group was 41% compared with 33% in the placebo group (P = 0.10). Thirty‐nine per cent of the STIs were associated with rectal infections. Overall, 81 participants (20%) acquired chlamydia infections during follow‐up, 88 (22%) acquired gonorrhea, 39 (10%) syphilis, and 5 (1%) hepatitis C virus infection. No participant acquired hepatitis B virus infection.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

TABLE 37: ADHERENCE TO INTERVENTION BASED ON PATIENT SELF‐REPORT FOR THE LAST SEXUAL INTERCOURSE % PrEP Use TDF/FTC Placebo Total (Min to Max) n = 649 Acts n = 563 Acts n = 1,212 Actsa Correct useb 45 (36 to 57) 40 (22 to 49) 43 (35 to 51) Suboptimal use 27 (14 to 35) 31 (18 to 44) 29 (20 to 38) No PrEP 27 (15 to 37) 29 (24 to 44) 28 (20 to 38)

TDF/FTC = tenofovir disoproxil fumarate/emtricitabine; max= maximum; min = minimum; PrEP = pre‐exposure prophylaxis. a 1,212 episodes of sexual intercourse were assessed in 319 participants. b Defined as at least one pill 24 hours before sex and one pill 24 hours after sex. Source: Molina et al.38

Safety A total of 186 (93%) participants in the treatment group and 181 (90%) in the placebo group reported any AE. Overall AEs were similar between groups; however, drug‐related gastrointestinal AEs were more common in the treatment group compared with the placebo group (14% versus 5%; P = 0.002), the most common being nausea, vomiting, diarrhea, abdominal pain, and other gastrointestinal disorders. In addition, elevations in serum creatinine levels were more common in the treatment group compared with the placebo group (18% versus 10%; P = 0.03). However, all but one of these events was grade 1, and none led to study drug discontinuation. Two participants (1%) in the treatment group had a decrease in creatinine clearance below 60 mL per minute. There were no significant differences in SAEs between treatment groups, and no deaths were reported. Detailed data outlining AEs are presented in Table 38.

TABLE 38: ADVERSE EVENTS Adverse Eventsa IPERGAY TDF/FTC (N = 199) Placebo (N = 201) Any AEs, n (%) 186 (93) 181 (90) Any SAEs, n (%) 20 (10) 17 (8) Death, n (%) 0 0 Any grade 3 or 4 event, n (%) 19 (10) 15 (7) Treatment discontinuation due to AEs, n (%) 1 (1) 0 Gastrointestinal AEs, n (%) 28 (14) 10 (5) Nausea 16 (8) 2 (1) Vomiting 3 (2) 0 Abdominal pain 13 (7) 3 (1) Diarrhea 8 (4) 6 (3) Other gastrointestinal disorder 1 (1) 2 (1) Bone fracture, n (%) 3 (2) 6 (3) Confirmed laboratory event, n (%) Elevated plasma creatinine Any grade 35 (18) 20 (10) Grade 1 35 (18) 19 (9) Grade 2 0 1 (< 1) Proteinuria ≥ 2+ 11 (6) 9 (4) Glycosuria ≥ 2+ 1 (1) 0 Elevated alanine aminotransferase 64

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

Adverse Eventsa IPERGAY TDF/FTC (N = 199) Placebo (N = 201) Any grade 33 (17) 26 (13) Grade 1 24 (12) 17 (8) Grade 2 8 (4) 5 (2) Grade 3 0 1 (< 1) Grade 4 1 (1) 3 (1)

AE = adverse event; TDF/FTC = tenofovir disoproxil fumarate/emtricitabine. a Adverse events reported for participants during the double‐blind phase of the study. Source: Molina et al.38

Limitations The intervention in the IPERGAY trial consisted of on‐demand use of FTC/TDF for PrEP, which is not a dosing regimen approved by Health Canada. In addition, the median number of pills of FTC/TDF taken during the IPERGAY trial does not correspond with the dosing regimen specified in the product monograph. Given the nature of the non‐daily dosing regimen of FTC/TDF in this trial, the dose of FTC/TDF using on‐demand therapy depends on incidence of sexual practice. In this study, the median number of pills taken was 15 per month, so it remains unclear whether FTC/TDF as PrEP would be efficacious for individuals who have sexual intercourse less frequently. Also, IPERGAY was designed as a DB RCT; however, as per request from the data and safety monitoring board, an unblinded interim analysis was conducted; consequently, the placebo group was discontinued and all the study participants were to be offered on‐demand PrEP. The median follow‐up was 9.3 months (IQR, 4.9 to 20.6), so the long‐term efficacy and safety of on‐demand FTC/TDF as PrEP is uncertain.

Summary The results of the IPERGAY study suggest that the use of TDF/FTC for on‐demand PrEP was associated with a reduction in the incidence of HIV‐1 seroconversion compared with placebo. Sexual behaviour appeared to remain constant over the course of the study period for patients in both groups, and treatment with TDF/FTC for on‐demand PrEP was generally well tolerated. Given the short‐term nature of the study and the use of an intermittent dosing regimen, caution is required when interpreting the results of this study.

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

REFERENCES

1. Summary: estimated of HIV incidence, prevalence and proportion undiagnosed in Canada, 2014 [Internet]. Ottawa: Public Health Agency of Canada; 2015. [cited 2016 Jun 16]. Available from: http://www.catie.ca/sites/default/files/2014‐HIV‐Estimates‐in‐Canada‐EN.pdf 2. Challacombe L. The epidemiology of HIV in Canada [Internet]. Toronto (ON): CATIE; 2015. [cited 2016 Apr 25]. Available from: http://www.catie.ca/fact‐sheets/epidemiology/epidemiology‐hiv‐canada 3. Gilead response to May 2, 2016 CDR request for additional information regarding the Truvada PrEP CDR review: details of absolute risk reduction data for iPrEx and Partner's PrEP trials [CONFIDENTIAL additional manufacturer's information]. Mississauga (ON): Gilead Sciences Canada, Inc.; 2016 May 12. 4. Clinical study report: CO‐US‐104‐0288. Chemoprophylaxis for HIV prevention in men [CONFIDENTIAL internal manufacturer's report]. Foster City (CA): Gilead Sciences, Inc.; 2011 Mar 24. 5. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med [Internet]. 2010 Dec 30 [cited 2016 Apr 1];363(27):2587‐99. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3079639/pdf/nihms264954.pdf 6. Clinical study report: CO‐US‐104‐0380. Parallel comparison of tenofovir and emtricitabine/tenofovir Pre‐Exposure Prophylaxis to prevent HIV‐1 acquisition within HIV‐1 discordant couples [CONFIDENTIAL internal manufacturer's report]. Foster City (CA): Gilead Sciences, Inc.; 2011 Nov 14. 7. Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med [Internet]. 2012 Aug 2 [cited 2016 Apr 1];367(5):399‐410. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770474/pdf/nihms493581.pdf 8. Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE, Segolodi TM, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med [Internet]. 2012 Aug 2 [cited 2016 Apr 1];367(5):423‐34. Available from: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1110711 9. About HIV/AIDS [Internet]. Atlanta (GA): Centers for Disease Control and Prevention; 2015 Dec 6. [cited 2016 Mar 18]. Available from: http://www.cdc.gov/hiv/basics/whatishiv.html 10. HIV transmission [Internet]. Atlanta (GA): Centers for Disease Control and Prevention; 2015 Dec 14. [cited 2016 Mar 18]. Available from: http://www.cdc.gov/hiv/basics/transmission.html 11. McCutchan FE. Global epidemiology of HIV. J Med Virol. 2006;78 Suppl 1:S7‐S12. 12. Pinkerton SD, Abramson PR. Effectiveness of condoms in preventing HIV transmission. Soc Sci Med. 1997 May;44(9):1303‐12. 13. Davis KR, Weller SC. The effectiveness of condoms in reducing heterosexual transmission of HIV. Fam Plann Perspect. 1999 Nov;31(6):272‐9. 14. HIV and AIDS in Canada: surveillance report to December 31, 2011 [Internet]. Ottawa: Public Health Agency of Canada; 2012. [cited 2016 Mar 18]. Available from: http://www.catie.ca/sites/default/files/PHAC_HIV‐AIDS_2011%20Report_Eng‐Fr.pdf 15. The Chief Public Health Officer's report on the state of public health in Canada, 2013. Infectious disease ‐ the never‐ending threat [Internet]. Ottawa: Public Health Agency of Canada; 2013. [cited 2016 Jun 16]. Available from: http://www.phac‐aspc.gc.ca/cphorsphc‐respcacsp/2013/sti‐its‐eng.php

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

16. Guidelines for the use of antiretroviral agents in HIV‐1‐infected adults and adolescents [Internet]. Rockville (MD): AIDSinfo; 2016 Jan 28. [cited 2016 Mar 17]. Available from: https://aidsinfo.nih.gov/guidelines/html/1/adult‐and‐adolescent‐treatment‐guidelines/0 17. Prevention [Internet]. Toronto: CATIE; 2016. [cited 2016 May 3]. Available from: http://www.catie.ca/en/prevention 18. Elion R, Coleman M. The preexposure prophylaxis revolution: from clinical trials to routine practice: implementation view from the USA. Curr Opin HIV AIDS. 2016 Jan;11(1):67‐73. 19. Preexposure prophylaxis for the prevention of HIV infection – 2014 : a clinical practice guideline [Internet]. Atlanta: Centers for Disease Control and Prevention; 2014 May 14. [cited 2016 May 3]. Available from: https://stacks.cdc.gov/view/cdc/23109 20. Consolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations [Internet]. Geneva: World Health Organization; 2014 Jul. [cited 2016 May 3]. Available from: http://apps.who.int/iris/bitstream/10665/128048/1/9789241507431_eng.pdf?ua=1&ua=1 21. Common Drug Review. CEDAC final recommendation and reasons for recommendation. Tenofovir/emtricitabine request for advice (Truvada® ‐ Gilead Sciences Canada, Inc.) [Internet]. Ottawa: CADTH; 2008. [cited 2016 May 3]. Available from: https://www.cadth.ca/sites/default/files/cdr/complete/cdr_truvada_rfa_complete‐dec17‐08.pdf 22. PrTruvada® (Emtricitabine/Tenofovir Disoproxil Fumarate) Tablets (200 mg/300 mg) Antiretroviral Agent [product monograph]. Mississauga (ON): Gilead Sciences Canada Inc.; 2016 Mar 24. 23. Deutsch MB, Glidden DV, Sevelius J, Keatley J, McMahan V, Guanira J, et al. HIV pre‐exposure prophylaxis in transgender women: a subgroup analysis of the iPrEx trial. Lancet HIV. 2015 Dec;2(12):e512‐e519. 24. Marcus JL, Glidden DV, Mayer KH, Liu AY, Buchbinder SP, Amico KR, et al. No evidence of sexual risk compensation in the iPrEx trial of daily oral HIV preexposure prophylaxis. PLoS ONE [Internet]. 2013 [cited 2016 Apr 1];8(12):e81997. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867330/pdf/pone.0081997.pdf 25. Solomon MM, Lama JR, Glidden DV, Mulligan K, McMahan V, Liu AY, et al. Changes in renal function associated with oral emtricitabine/tenofovir disoproxil fumarate use for HIV pre‐exposure prophylaxis. AIDS [Internet]. 2014 Mar 27 [cited 2016 Apr 12];28(6):851‐9. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966916/pdf/aids‐28‐851.pdf 26. CDR submission: TRUVADA® (emtricitabine / tenofovir disoproxil fumarate) Company: Gilead Sciences Canada Inc. [CONFIDENTIAL manufacturer's submission]. Mississauga (ON): Gilead Sciences Canada Inc.; 2016 Mar 9. 27. Health Canada reviewer's report: TRUVADA (emtricitabine + tenofovir disoproxil fumarate) [CONFIDENTIAL internal report]. Ottawa: Therapeutics Products Directorate, Health Canada; 2016 Feb 22. 28. Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Medical review(s). In: Truvada® (emtricitabine/tenofovir disoproxil fumarate) 200 mg emtricitabine/300 mg tenofovir disoproxil fumarate oral fixed‐dose combination tablet. Company: Gilead Sciences Inc. Application No.: NDA 21‐752/S‐30. Approval Date: 8/02/2004 [Internet]. Rockville (MD): FDA; 2004 [cited 2016 May 4]. (FDA approval package). Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/021752s000_TruvadaTOC.cfm 29. Mugwanya KK, Wyatt C, Celum C, Donnell D, Mugo NR, Tappero J, et al. Changes in glomerular kidney function among HIV‐1‐uninfected men and women receiving emtricitabine‐tenofovir disoproxil

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

fumarate preexposure prophylaxis: a randomized clinical trial. JAMA Intern Med [Internet]. 2015 Feb [cited 2016 Apr 1];175(2):246‐54. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354899/pdf/nihms665731.pdf 30. Mujugira A, Baeten JM, Donnell D, Ndase P, Mugo NR, Barnes L, et al. Characteristics of HIV‐1 serodiscordant couples enrolled in a clinical trial of antiretroviral pre‐exposure prophylaxis for HIV‐1 prevention. PLoS ONE [Internet]. 2011 [cited 2016 Apr 12];6(10). Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3187805/pdf/pone.0025828.pdf 31. Celum C, Wald A, Lingappa JR, Magaret AS, Wang RS, Mugo N, et al. Acyclovir and transmission of HIV‐ 1 from persons infected with HIV‐1 and HSV‐2. N Engl J Med [Internet]. 2010 Feb 4 [cited 2018 Mar 7];362(5):427‐39. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2838503 32. Montaner J, Guillemi S, Harris M. Therapeutic guidelines for antiretroviral (ARV) treatment of adult HIV infection [Internet]. Vancouver: British Columbia Centre for Excellence in HIV/AIDS; 2015. [cited 2016 May 17]. Available from: http://www.cfenet.ubc.ca/sites/default/files/uploads/Guidelines/bc‐cfe‐art‐ guidelines‐Oct_14_2015.pdf 33. Patterson KB, Prince HA, Kraft E, Jenkins AJ, Shaheen NJ, Rooney JF, et al. Penetration of tenofovir and emtricitabine in mucosal tissues: implications for prevention of HIV‐1 transmission. Sci Transl Med [Internet]. 2011 Dec 7 [cited 2016 May 31];3(112):112re4. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3483088 34. Haberer JE, Baeten JM, Campbell J, Wangisi J, Katabira E, Ronald A, et al. Adherence to antiretroviral prophylaxis for HIV prevention: a substudy cohort within a clinical trial of serodiscordant couples in east Africa. PLoS Med [Internet]. 2013 [cited 2016 Apr 12];10(9). Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769210/pdf/pmed.1001511.pdf 35. Marrazzo JM, Ramjee G, Richardson BA, Gomez K, Mgodi N, Nair G, et al. Tenofovir‐based preexposure prophylaxis for HIV infection among African women. N Engl J Med [Internet]. 2015 Feb 5 [cited 2016 Apr 1];372(6):509‐18. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4341965/pdf/nihms665389.pdf 36. Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med [Internet]. 2012 Aug 2 [cited 2016 Apr 1];367(5):411‐22. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3687217/pdf/nihms475869.pdf 37. Corneli AL, McKenna K, Perry B, Ahmed K, Agot K, Malamatsho F, et al. The science of being a study participant: FEM‐PrEP participants' explanations for overreporting adherence to the study pills and for the whereabouts of unused pills. J Acquir Immune Defic Syndr. 2015;68(5):578‐84. 38. Molina JM, Capitant C, Spire B, Pialoux G, Cotte L, Charreau I, et al. On‐demand preexposure prophylaxis in men at high risk for HIV‐1 infection. N Engl J Med. 2015 Dec 3;373(23):2237‐46. 39. Mutua G, Sanders E, Mugo P, Anzala O, Haberer JE, Bangsberg D, et al. Safety and adherence to intermittent pre‐exposure prophylaxis (PrEP) for HIV‐1 in African men who have sex with men and female sex workers. PLoS ONE [Internet]. 2012 [cited 2016 Apr 1];7(4):e33103, 2012. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325227/pdf/pone.0033103.pdf 40. McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, et al. Pre‐exposure prophylaxis to prevent the acquisition of HIV‐1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open‐label randomised trial. Lancet [Internet]. 2016 Jan 2 [cited 2016 Apr 1];387(10013):53‐ 60. Available from: http://www.sciencedirect.com/science/article/pii/S0140673615000562 41. Dolling DI, Desai M, McOwan A, Gilson R, Clarke A, Fisher M, et al. An analysis of baseline data from the PROUD study: an open‐label randomised trial of pre‐exposure prophylaxis. Trials [Internet]. 2016 [cited

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

2016 Apr 1];17(1):163. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806447/pdf/13063_2016_Article_1286.pdf 42. Mayer KH, Ramjee G. The current status of the use of oral medication to prevent HIV transmission. Curr Opin HIV AIDS. 2015;10(4):226‐32. 43. Mugwanya KK, Wyatt C, Celum C, Donnell D, Kiarie J, Ronald A, et al. Reversibility of glomerular renal function decline in HIV‐uninfected men and women discontinuing emtricitabine‐tenofovir disoproxil fumarate pre‐exposure prophylaxis. J Acquir Immune Defic Syndr. 2016 Apr 1;71(4):374‐80. 44. Mulligan K, Glidden DV, Anderson PL, Liu A, McMahan V, Gonzales P, et al. Effects of Emtricitabine/Tenofovir on Bone Mineral Density in HIV‐Negative Persons in a Randomized, Double‐ Blind, Placebo‐Controlled Trial. Clin Infect Dis. 2015 Aug 15;61(4):572‐80. 45. Kasonde M, Niska RW, Rose C, Henderson FL, Segolodi TM, Turner K, et al. Bone mineral density changes among HIV‐uninfected young adults in a randomised trial of pre‐exposure prophylaxis with tenofovir‐emtricitabine or placebo in Botswana. PLoS ONE [Internet]. 2014 [cited 2016 Apr 12];9(3). Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953113/pdf/pone.0090111.pdf 46. Auvert B, Taljaard D, Lagarde E, Sobngwi‐Tambekou J, Sitta R, Puren A. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med [Internet]. 2005 Nov [cited 2016 Jun 1];2(11):e298. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1262556 47. Bailey RC, Moses S, Parker CB, Agot K, Maclean I, Krieger JN, et al. Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial. Lancet. 2007 Feb 24;369(9562):643‐56. 48. Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S, Nalugoda F, et al. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet. 2007 Feb 24;369(9562):657‐66. 49. Stillwaggon E, Sawers L. Rush to judgment: the STI‐treatment trials and HIV in sub‐Saharan Africa. J Int AIDS Soc [Internet]. 2015 [cited 2016 Jun 1];18:19844. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438085 50. Otten RA, Smith DK, Adams DR, Pullium JK, Jackson E, Kim CN, et al. Efficacy of postexposure prophylaxis after intravaginal exposure of pig‐tailed macaques to a human‐derived retrovirus (human immunodeficiency virus type 2). J Virol [Internet]. 2000 Oct [cited 2016 Jun 1];74(20):9771‐5. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC112413 51. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O'Sullivan MJ, et al. Reduction of maternal‐infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994 Nov 3;331(18):1173‐80. 52. Cardo DM, Culver DH, Ciesielski CA, Srivastava PU, Marcus R, Abiteboul D, et al. A case‐control study of HIV seroconversion in health care workers after percutaneous exposure. Centers for Disease Control and Prevention Needlestick Surveillance Group. N Engl J Med. 1997 Nov 20;337(21):1485‐90. 53. Schechter M, do Lago RF, Mendelsohn AB, Moreira RI, Moulton LH, Harrison LH, et al. Behavioral impact, acceptability, and HIV incidence among homosexual men with access to postexposure chemoprophylaxis for HIV. J Acquir Immune Defic Syndr. 2004 Apr 15;35(5):519‐25. 54. Kahn JO, Martin JN, Roland ME, Bamberger JD, Chesney M, Chambers D, et al. Feasibility of postexposure prophylaxis (PEP) against human immunodeficiency virus infection after sexual or injection drug use exposure: the San Francisco PEP Study. J Infect Dis. 2001 Mar 1;183(5):707‐14. 55. Heuker J, Sonder GJ, Stolte I, Geskus R, van den HA. High HIV incidence among MSM prescribed postexposure prophylaxis, 2000‐2009: indications for ongoing sexual risk behaviour. AIDS. 2012 Feb 20;26(4):505‐12. 69

Common Drug Review August 2016 CDR CLINICAL REVIEW REPORT FOR TRUVADA

56. Mayer KH. PrEP 2015: state of the science [Slide deck on the Internet]. Washington (DC): International Association of Providers of AIDS Care (IAPAC); 2015 [cited 2018 Apr 20]. (Presented at IAPAC. Paris 2015 Oct 1‐2). Available from: http://www.iapac.org/tasp_prep/presentations/TPSparis15‐Plenary‐ Mayer.pdf Registration required. 57. The epidemiology of HIV in gay men and other men who have sex with men [Internet]. Toronto: Canada's Source for HIV and Hepatitis C Information (CATIE); 2016. [cited 2016 May 31]. Available from: http://www.catie.ca/en/fact‐sheets/epidemiology/epidemiology‐hiv‐gay‐men‐and‐other‐men‐ who‐have‐sex‐men 58. Baeten JM, Donnell D, Mugo NR, Ndase P, Thomas KK, Campbell JD, et al. Single‐agent tenofovir versus combination emtricitabine plus tenofovir for pre‐exposure prophylaxis for HIV‐1 acquisition: an update of data from a randomised, double‐blind, phase 3 trial. Lancet Infect Dis [Internet]. 2014 Nov [cited 2016 Apr 1];14(11):1055‐64. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252589/pdf/nihms635147.pdf 59. Buchbinder SP, Glidden DV, Liu AY, McMahan V, Guanira JV, Mayer KH, et al. HIV pre‐exposure prophylaxis in men who have sex with men and transgender women: a secondary analysis of a phase 3 randomised controlled efficacy trial. Lancet Infect Dis [Internet]. 2014 Jun [cited 2016 Apr 1];14(6):468‐ 75. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133171/pdf/nihms600835.pdf 60. Murnane PM, Celum C, Mugo N, Campbell JD, Donnell D, Bukusi E, et al. Efficacy of preexposure prophylaxis for HIV‐1 prevention among high‐risk heterosexuals: subgroup analyses from a randomized trial. AIDS [Internet]. 2013 Aug 24 [cited 2016 Apr 1];27(13):2155‐60. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3882910/pdf/nihms505879.pdf 61. Clinical study report addendum 2011 for study: CO‐US‐104‐0288. Chemophrophylaxis for HIV prevention in men [CONFIDENTIAL internal manufacturer's report]. Foster City (CA): Gilead Sciences, Inc.; 2011 Nov 15.

Common Drug Review August 2016